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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 107  |  Issue : 3  |  Page : 200-204

A study comparing ranibizumab monotherapy versus ranibizumab plus dexamethasone combination therapy for treatment of diffuse diabetic macular edema


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

Date of Submission05-Jun-2014
Date of Acceptance10-Aug-2014
Date of Web Publication30-Dec-2014

Correspondence Address:
Ahmed M Abdel Hadi
24 Fawzy Moaz Street, Safwa 5, Entrance 2, 21311, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.148174

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  Abstract 

Purpose
The aim of the study was to evaluate the hypothesis that combination therapy of intravitreal ranibizumab and dexamethasone would be more effective than ranibizumab monotherapy in patients with diffuse diabetic macular edema (DME).
Patients and methods
The study included 24 eyes of 24 patients with center-involved DME. The study included eyes with central foveal thickness greater than 300 μm on cross-hair protocol, diffuse macular thickening of greater than two disc-areas on slit-lamp biomicroscopy. Eligible study participants in this prospective, nonrandomized, comparative, interventional case series were divided into two groups. The first group was chosen to receive 0.5 mg/0.05 ml ranibizumab, whereas the other group was chosen to receive 0.4 mg/0.1 ml intravitreal dexamethasone (IVD) and 0.5 mg/0.05 ml ranibizumab. Exclusion criteria included: (a) eyes with previous treatments (such as focal laser therapy, vitrectomy, and intravitreal injection of triamcinolone or antivascular endothelial growth factor injections) beyond a 6-month period; (b) evidence of proliferative diabetic retinopathy on fundus fluorescein angiography or clinical examination; (c) any evidence of macular ischemia on fundus fluorescein angiography; (d) presence of a taut posterior hyaloid, vitreomacular traction or epiretinal membrane on optical coherence tomography (OCT); and (e) presence of subfoveal hard exudates. All patients were followed up for 6 weeks postinjection; changes of retinal thickness, visual acuity, and intraocular pressure were evaluated.
Results
Twelve eyes of 12 patients were treated with ranibizumab (group 1), and 12 eyes of another 12 patients were treated with IVD + ranibizumab (group 2). In group 1, the postinjection central macular thickness showed a statistically significant improvement from a baseline of 500.1 ± 40.1 to 456.7 ± 28.4 μm (reduction of 43.4 μm, P < 0.001) at 6 weeks. Similarly, the postinjection best-corrected visual acuity (BCVA) showed a trend toward improvement from a baseline of 0.17 to 0.22 at 6 weeks. In group 2, the postinjection central macular thickness showed a statistically significant improvement from a baseline of 508.4 ± 36.4 to 468.1 ± 33.1 μm (reduction of 40.3 μm, P < 0.001) at 6 weeks. Similarly, the postinjection BCVA showed a trend toward improvement from a baseline of 0.17 to 0.21 at 6 weeks. The difference in postinjection intraocular pressure, BCVA, and central macular thickness between the two groups at 6 weeks was not statistically significant.
Conclusion
A single injection of intravitreal ranibizumab (IVR) demonstrated similar efficacy compared with IVD + ranibizumab in terms of OCT macular thickness reduction in selected cases of diffuse DME after 6-week follow-up.

Keywords: central macular thickness, diabetic macular edema, intravitreal dexamethasone, intravitreal ranibizumab, spectral domain optical coherence tomography


How to cite this article:
Abdel Hadi AM. A study comparing ranibizumab monotherapy versus ranibizumab plus dexamethasone combination therapy for treatment of diffuse diabetic macular edema. J Egypt Ophthalmol Soc 2014;107:200-4

How to cite this URL:
Abdel Hadi AM. A study comparing ranibizumab monotherapy versus ranibizumab plus dexamethasone combination therapy for treatment of diffuse diabetic macular edema. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2019 Aug 19];107:200-4. Available from: http://www.jeos.eg.net/text.asp?2014/107/3/200/148174


  Introduction Top


Diabetic macular edema (DME) is a leading cause of visual impairment in diabetic patients [1], and its prevalence has been reported to be 10% [2]. Although focal laser treatment is effective, 12% of treated eyes nevertheless have moderate vision loss 3 years following treatment. Furthermore, eyes with diffuse DME with cystic changes had a poorer response to grid laser photocoagulation [3]. Hence, there remains a great need for additional effective therapies for these eyes.

Intravitreal triamcinolone (IVT) shows to have a beneficial effect on DME [4,5], with a probable mechanism of increase in tight junction proteins, which diminish vessel leakage by a local vasoconstrictive effect [6,7]. The side effect profile of IVTA, which includes increased intraocular pressure (IOP) and cataract progression, made retina specialists search for an alternative agent as initial therapy that would achieve efficacy similar to IVTA without incurring these potential side effects [8-10].

Dexamethasone has been shown to inhibit vascular leakage induced by vascular endothelial growth factor (VEGF) in animal models of inflammation and diabetes [11]. Dexamethasone (dexamethasone sodium phosphate) is a synthetic glucocorticoid formulation with a higher anti-inflammatory potency profile when compared with triamcinolone acetonide [12]. Intravitreal dexamethasone (IVD) has been used in the treatment of endophthalmitis and as an adjunct during vitrectomy in patients with diabetes at doses as high as 0.8 mg without any significant ocular toxicity [13,14]. Dexamethasone also lacks direct toxicity to the retinal pigment epithelium, which is seen with triamcinolone [15].

Ultrashort-acting intravitreal steroids such as dexamethasone have less of an effect on IOP rise and cataract progression. However, they also tend to have less of an effect on the reduction of DME [16].

Ranibizumab is a fully humanized monoclonal antibody fragment (Fab), which binds to multiple variant of VEGF-A [17], and is approved for the treatment of neovascular age-related macular degeneration. The expression of VEGF is elevated in DME. Ranibizumab binds to and inhibits multiple VEGF variants. The ranibizumab for edema of the macula in diabetes (READ-2) showed that ranibizumab had a significantly better visual acuity (VA) outcome than macular laser photocoagulation (MPC) at 6, 18 months, and 2 years [18]. In a recent published study by http://DRCR.net, it was reported that intravitreal ranibizumab with prompt or deferred laser was more effective compared with MPC alone through at least 1 year [19].

Nevertheless, a study by Paccola and colleagues showed that a single intravitreal injection of triamcinolone may offer certain advantages over anti-VEGF injections (bevacizumab in this study) in the short-term management of refractory DME, specifically with respect to changes in central macular thickness. Best-corrected visual acuity (BCVA) was significantly higher at weeks 8 and 12 in the IVT group compared with that in the anti-VEGF group [20].

In this prospective randomized trial, we tried to evaluate the hypothesis that combination therapy of intravitreal ranibizumab and dexamethasone would be more effective than ranibizumab monotherapy in patients with diffuse DME.


  Patients and methods Top


The study included 24 eyes of 24 patients with center-involved DME. The study was carried out at a tertiary referral center in Alexandria, Egypt. Before screening, all patients provided written informed consent after thorough explanation of the procedure. The protocol was approved by the local ethics committee. The enrollment period extended over 9 months.

Eligible study participants in this prospective, nonrandomized, comparative, interventional case series were divided into two groups. The first group was chosen to receive 0.5 mg/0.05 ml ranibizumab, whereas the other group was chosen to receive 0.4 mg/0.1 ml IVD and 0.5 mg/0.05 ml ranibizumab.

The study included eyes with central foveal thickness greater than 300 μm on cross-hair protocol, diffuse macular thickening of greater than two disc-areas on slit-lamp biomicroscopy. These cases were included independent of the age, metabolic control, and type of diabetes.

Exclusion criteria included:

(a) Eyes with previous treatments (such as focal laser therapy, vitrectomy, and intravitreal injection of triamcinolone or antivascular endothelial growth factor injections) beyond a 6-month period;

(b) Evidence of proliferative diabetic retinopathy on fundus fluorescein angiography or clinical examination;

(c) Any evidence of macular ischemia on fundus fluorescein angiography;

(d) Presence of a taut posterior hyaloid, vitreomacular traction or epiretinal membrane on OCT;

(e) Presence of subfoveal hard exudates;

(f) Any other ocular cause that in the opinion of the investigator would interfere with BCVA, such as significant cataract, glaucoma, age-related macular degeneration, branch retinal vein occlusion, etc; and

(f) Personal history of previous thromboembolic events.

At the initial visit, patients underwent complete eye examination, including determination of BCVA using a decimal chart, slit-lamp examination, IOP measurement, stereoscopic biomicroscopy of the macula, retinal thickness measurement by optical coherence tomography (obtained from a single spectral domain OCT machine, FA, and fundus photography). All patients were followed up for 6 weeks postinjection; changes of retinal thickness, visual acuity, and IOP were evaluated.

Statistical analysis

Only one eye per patient was treated. All data were collected on a MS-Excel 2000 spreadsheet (Microsoft Corporation, Redmond, Washington, USA) and analyzed using SPSS 20.0 for Windows (SPSS Inc., Chicago, Illinois, USA). All tests were two tailed and set at P-value of significance less than 0.05.


  Results Top


Twelve eyes of 12 patients were treated with ranibizumab (group1), and 12 eyes of another 12 patients were treated with IVD + ranibizumab (group 2). In group 1, all 12 patients were pseudophakic with a baseline IOP of 13.65 mmHg. In group 2, five patients were phakic. The seven remaining patients were pseudophakic with a mean baseline IOP of 13.3 mmHg. None of the study patients was lost to follow-up for the 6-week duration of the study. The mean age was 60 ± 4.4 years in group 1 and 59.1 ± 4.6 years in group 2. The comparisons of means between the two groups before injection and after 6 weeks of injection are shown in [Table 1].
Table 1 Summary of the group means with respect to age, sex, VA before and after injection, IOP before and after injection, and CMT before and after injection


Click here to view


In group 1, the postinjection central macular thickness showed a statistically significant improvement from a baseline of 500.1 ± 40.1 to 456.7 ± 28.4 μm (reduction of 43.4 μm, P < 0.001) at 6 weeks. Similarly, the postinjection BCVA showed a trend toward improvement from a baseline of 0.17 to 0.22 at 6 weeks. In group 2, the postinjection central macular thickness showed a statistically significant improvement from a baseline of 508.4 ± 36.4 to 468.1 ± 33.1 μm (reduction of 40.3 μm, P < 0.001) at 6 weeks. Similarly, the postinjection BCVA showed a trend toward improvement from a baseline of 0.17 to 0.21 at 6 weeks ([Table 2]).
Table 2 Outcomes of the two groups with respect to VA, IOP, and CMT after treatment


Click here to view


The difference in postinjection IOP [Figure 1] between the two groups at 6 weeks was not statistically significant. The difference in postinjection BCVA [Figure 2] between the two groups at 6 weeks was not statistically significant (P = 0.0066) ([Table 1]). The difference in postinjection macular thickness [Figure 3] between the two groups at 6 weeks was not statistically significant (P = 0.159).

No patients in both groups had IOP elevations greater than 21 mmHg during the study period nor did any patients require anterior chamber paracentesis for loss of retinal perfusion after injections. No instances of endophthalmitis, noninfectious intraocular inflammation, retinal tear, or retinal detachment were seen. None of the cases had cataract progression as per lens opacity classification during the follow-up period.
Figure 1: Box plot showing the distribution of the IOP in the two groups before injection (blue) and after 6 weeks from injection (green). IOP, intraocular pressure.

Click here to view
Figure 2: Box plot showing the distribution of the VA in the two groups before injection (blue) and after 6 weeks from injection (green).

Click here to view
Figure 3: Box plot showing the distribution of the CMT in the two groups before injection (blue) and after 6 weeks from injection (green). CMT, central macular thickness.

Click here to view



  Discussion Top


Intravitreal injection of steroids has gained a wide acceptance and is being used as an off-label treatment option for management of macular edema from various retinopathies [8,21]. Despite the rapid and wide acceptance of this treatment modality, the optimal dose, case selection criteria, safety, and efficacy of intravitreal steroids are not well known, as large randomized clinical trial results are currently lacking.

In the current study, we utilized dexamethasone 500 mg in 0.05 ml followed by intravitreal ranibizumab 0.5 mg in 0.05 ml (group 2). Although dexamethasone has a short half-life compared with triamcinolone, a recent study made the point that intravitreal medications can be clinically effective, despite half-lives that are variable and much shorter than the therapeutic treatment interval [22]. Specifically, a potent drug that acutely suppresses inflammation in pulses may be more effective than a less acutely potent drug that has a longer activity curve.

This study is the first to compare directly the use of a combination of IVD + ranibizumab with ranibizumab as a monotherapy in patients with DME in terms of efficacy and safety. This pilot study represents a preliminary evaluation of the hypothesis that dexamethasone's unique anti-inflammatory properties could provide a useful adjunct to the treatment of diffuse DME in combination with intravitreal ranibizumab.

In group 1 (ranibizumab), the postinjection central macular thickness showed a statistically significant improvement from a baseline of 500.1 ± 40.1 to 456.7 ± 28.4 μm (reduction of 43.4 μm, P < 0.001) at 6 weeks. Similarly, the postinjection BCVA showed a trend toward improvement from a baseline of 0.17 to 0.22 at 6 weeks. Similarly, the postinjection central macular thickness in group 2 (IVD + ranibizumab) showed a statistically significant improvement from a baseline of 508.4 ± 36.4 to 468.1 ± 33.1 μm (reduction of 40.3 μm, P < 0.001) at 6 weeks. In addition, the postinjection BCVA showed a trend toward improvement from a baseline of 0.17 to 0.21 at 6 weeks.

As expected in this small pilot study, most of these differences were not statistically significant. The difference in postinjection macular thickness between the two groups at 6 weeks was not statistically significant (P = 0.159). The difference in postinjection BCVA between the two groups at 6 weeks was again not statistically significant (P = 0.0066). The difference in postinjection IOP between the two groups at 6 weeks was not statistically significant (P = 0.09).

Soheilian et al. [23] found that combination therapy with IVTA and IVA demonstrated no additional benefit when compared with IVA alone.

Ollendorf and colleagues reported in their work that no statistically significant and/or consistent differences were found between anti-VEGF agents used for treatment of eyes with DME with respect to BCVA changes or the percentage of patients gaining more than 10 letters. No discernible differences in the potential harms of anti-VEGFs, including ocular events, myocardial infarction, stroke, and other cardiovascular events, as well as death, were noted between aflibercept, pegaptanib, and ranibizumab. Data on harms for bevacizumab were under-reported [24].

In a prospective, randomized clinical trial by Faghihiand colleagues, including 130 eyes of 110 patients with type 2 diabetes suffering from DME, eligible eyes were randomly assigned to 1.25 mg intravitreal bevacizumab (42 eyes) (the IVB group) or combination of 1.25 mg bevacizumab and 2 mg triamcinolone acetonide (41 eyes) (the IVB + IVT group) or MPC (47 eyes). At week 6, all three groups showed significant reduction in CMT but the reductions for IVB and IVB + IVT were significantly more than macular photocoagulation (P < 0.001) [25]. Taking into consideration the difference in the study design, we can pinpoint that IVB, an anti-VEGF agent shown to bear no difference with IVR with respect to efficacy in case of DME [24], showed no statistically different results as compared with IVTA + IVB at 6 weeks.

Similarly, no significant macular volume change or improvement in BCVA was observed in the study by Sheth and colleagues, in the IVA (intravitreal avastin) group, although supplemented with IVD. They investigated a possibility that IVD + avastin could have shown a very immediate significant reduction in macular volume (1-week or 2-week follow-up) because of the ultrashort-acting nature of dexamethasone, but this was not the case. In the latter study, the OCT measurements were taken at weekly intervals for the first 4 weeks and none showed a significant reduction in macular volume [26].

Weaknesses of this study include small sample size. It was also limited by the available budget. The primary goal of this study, being a pilot study, was to identify signals that might warrant further work on this research point, and we believe that the current study did so. The absence of a longer follow-up remains a limitation of the current study. Moreover, some may argue in favor of administering multiple injections of IVD + ranibizumab to achieve a progressive reduction in macular thickening and attain an OCT appearance more suitable to treatment with focal grid laser. Keeping in mind the off-label use of IVD and the short duration of action of IVR, we did not consider using multiple injections of any agent.


  Conclusion Top


A single injection of IVR demonstrated similar efficacy compared with IVD + ranibizumab in terms of OCT macular thickness reduction in select cases of diffuse DME after 6-week follow-up.


  Acknowledgements Top


 
  References Top

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