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• Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase lll trials
  Mihai Calugaru
  Published on: 17 August 2016
• Re:Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials
  Ronald P. Danis
  Published on: 20 July 2016
• Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials
  Jagat Ram
  Published on: 7 June 2016

• Published on: 17 August 2016

  Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase lll trials

  • Mihai Calugaru, Professor Univ
  • Other Contributors:
    • Dan Calugaru

  Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema; a pooled analysis of 3-year phase lll trials Dan Calugaru, Mihai Calugaru Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania Re: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase lll trials. Danis et al Br J Ophthalmol 2016;100:796-801.

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  Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema; a pooled analysis of 3-year phase lll trials Dan Calugaru, Mihai Calugaru Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania Re: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase lll trials. Danis et al Br J Ophthalmol 2016;100:796-801.

  Dear Editor We would like to address several challenges arisen from the study by Danis et al (1) and which can be specifically summarized as follows:

  1. There was a selection bias owing to the inclusion in the study of both the treatment-na?ve patients and those with previous treatments (focal/grid laser, intravitreal steroid, and specific anti-vascular endothelial growth factor [VEGF] agents).

  2. Although the final central subfield retinal thickness (CSRT) values of the two dexamethasone implant (DEX implant; Ozurdex Allergan, Irvine, California, USA) groups (eg, 345.7 and 339 microns in the DEX implant 0.7 mg and DEX implant 0.35 mg groups, respectively) were significantly reduced in comparison with the sham group (398.8 microns) yet the structural outcomes of this study were poor. Of note, all these CSRT values are much more than the cutoff (252 microns) for the upper level of the normal CSRT (212 +/-20 microns) plus 2 standard deviations (2). The persistence of high values of the CSRT as well as the high proportions of study eyes with CSRT > 250 microns at the final visit (eg, 60.2 %, 58.7%, and 71.6% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively) highlight unresolved macular edema due to insufficient macular deturgescence and indicate that the disease process is still active and progressive requiring further treatment with anti-angiogenic agents.

  3. The final unsatisfactory anatomic results of this study could be explained by the low frequency of injections (a median of four to five injections over a 3-year period) and the long-standing duration of diabetic macular oedema (DME) (between 23.6 and 25.9 months in the three groups of patients). These facts promoted the delayed occurrence of a permanent retinal capillaropathy owing to permanent breakdown of the inner and outer endothelial blood-retinal barriers. However, this condition is incurable due to the ischemic irreversible lesions to the macular retinal ganglion cell complex, close to the foveola, with macular oedema being a minor factor. The saw-tooth pattern of the profile of mean change in CSRT versus time highlights the fact that the authors have not taken into account the currently valid recommendations that the duration of ? 3-line improvement after DEX implant is typically 2-3 months (3), and that reinjections generally will be performed after 4-5 months (4). If these assertions had been considered, the design and outcomes of the present study would have been completely different.

  Altogether, regardless of the intravitreal pharmacotherapy chosen, namely, specific or nonspecific (DEX implant) anti-VEGF agents, the efficacy of treatment depends primarily on the promptness of the therapy after DME onset. Both groups of anti-VEGF substances provide similar rates of vision improvement but with superior anatomic outcomes and fewer injections in the DEX implant-treated eyes. However, more patients receiving the DEX implant lose vision mainly due to cataract.

  References 1. Danis RP, Sadda S, Li XY, et al. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3- year phase lll trials. Br J Ophthalmol 2016; 100:796-801. 2. Chan A, Duker JS, Ko TH, et al. Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. Arch Ophthalmol 2006;124;193-198. 3. Kuppermann BD, Haller JA, Bandello F. Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion. Retina 2014;34:1743-1749. 4. Coscas G, Augustin A, Bandello F, et al. Retreatment with Ozurdex for macular edema secondary to retinal vein occlusion. Eur J Ophthalmol 2014;24:1-9.

  Conflict of interest: None declared

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• Published on: 20 July 2016

  Re:Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials

  • Ronald P. Danis, Director, Fundus Photograph Reading Center
  • Other Contributors:
    • Srinivas Sadda, Xiao-Yan Li, Harry Cui, Yehia Hashad, and Scott M. Whitcup

  Dear Editor, We thank Drs Gupta and Ram for their interest in our recent paper on the anatomical effects of dexamethasone intravitreal implant (DEX implant) in eyes with diabetic macular oedema [1] and appreciate the opportunity to respond to their comments. Their letter highlights various patient- and treatment-related factors that potentially might have influenced the retinal findings described in our analysis. We pro...

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  Dear Editor, We thank Drs Gupta and Ram for their interest in our recent paper on the anatomical effects of dexamethasone intravitreal implant (DEX implant) in eyes with diabetic macular oedema [1] and appreciate the opportunity to respond to their comments. Their letter highlights various patient- and treatment-related factors that potentially might have influenced the retinal findings described in our analysis. We provide here some further clarification on the specific points raised in their letter. Firstly, the MEAD study data do not allow us to determine with certainty the treatment-free interval preceding DEX implant injection. However, we can confirm that all enrolled patients were required to discontinue intravitreal anti-VEGF and triamcinolone treatment at least 3 and 6 months, respectively, prior to study entry. Also, ranibizumab was not available at the start of the study (2004) and only 7% of patients had received prior anti-VEGF therapy. Moreover, randomization is likely to have minimized any imbalance between the treatment groups. Secondly, patients presenting with epiretinal membrane or vitreomacular traction syndrome at the initial screening visit were excluded from study entry. Thirdly, regarding the issue of insulin and oral hypoglycaemic use and changes in antidiabetic treatment during the study, randomization presumably minimized any influence these factors might have had on study outcomes. Fourthly, the study was not designed to assess the comparative efficacy of the 0.35 mg and 0.7 mg implants. However, since HbA1c assays over the course of the study showed no significant difference in glycaemic control between the three treatment arms, the MEAD findings indicate that the two implants are of comparable efficacy in reducing macular oedema. Finally, for information on the effects of DEX implant on lens status the reader is referred to the primary paper of the MEAD Study Group [2].

  Ronald P. Danis, M.D. Srinivas Sadda, M.D. Xiao-Yan Li, M.D. Harry Cui, MS. Yehia Hashad, M.D. Scott M. Whitcup, M.D.

  Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2870 University Avenue, Madison, Wisconsin 53711. E-mail: rpdanis@wisc.edu

  References 1. Danis RP, Sadda S, Li XY, et al. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3- year phase III trials. Br J Ophthalmol 2016;100:796-801. 2. Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham- controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904-14.

  Conflict of Interest:

  RPD and SS have received grant support and consulting fees from Allergan, Inc. X-YL and YH are employees of Allergan, Inc.

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  Conflict of Interest:
  None declared.

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• Published on: 7 June 2016

  Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials

  • Jagat Ram, Professor and Head
  • Other Contributors:
    • Parul Chawla Gupta

  eLetter Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials Parul Chawla Gupta, MS; Jagat Ram, MS, FAMS Department of Ophthalmology Post Graduate Institute of Medical Education and Research, Chandigarh, India, 160012 Corresponding author Dr. Jagat Ram, MS, FAMS Professor and Head Department of Ophthalmology Post Graduate Institute of M...

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  eLetter Comment on: Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials Parul Chawla Gupta, MS; Jagat Ram, MS, FAMS Department of Ophthalmology Post Graduate Institute of Medical Education and Research, Chandigarh, India, 160012 Corresponding author Dr. Jagat Ram, MS, FAMS Professor and Head Department of Ophthalmology Post Graduate Institute of Medical Education and Research, Chandigarh, India, 160012 Email id: drjagatram@gmail.com Conflict of interest and source of funding- None declared

  Dear Editor, We read with interest the recent paper by Danis [1] and associates assessing the long-term effects of dexamethasone intravitreal implant (DEX implant) monotherapy on retinal morphology in diabetic macular edema (DME). While the study is indeed interesting, there are certain points we wish to highlight. Firstly, among the previously treated eyes what was the mean interval between DEX injection and any previous treatment since it may confound the results. A recent study by Chhablani [2] et al, showed significant difference (P= 0.016) between the longest treatment-free interval between the groups that is, 10.5? 7.8 and 7.0? 4.4 months among treatment naive and previously treated eyes, respectively. What was the longest treatment-free interval in previously treated and na?ve eyes post DEX implant in the present study? Secondly, how many patients had vitreomacular traction syndrome or epiretinal membrane? Thirdly, in a meta-analysis of observational studies carried out by Zhang and colleagues [3] evaluating the effect of insulin use on the risk of developing macular edema, it was seen that insulin use increased the risk of macular edema. In few studies [3, 4], the risk for macular edema was greater in patients receiving pioglitazone/rosiglitazone than in those who did not. In addition, combining pioglitazone with insulin was associated with an even greater risk for macular edema, with patients having a more than 11-fold increased risk compared with diabetic patients who did not receive the 2 drugs. Hence, the authors need to take into account the number of patients on oral hypoglycemic like pioglitazone/rosiglitazone and those who shifted to insulin therapy during follow up. History of aspirin use and ACE inhibitor use should be enquired as they are shown to be associated with a reduced risk of DME. Fourthly, "at the final study visit, the decline in the proportion of study eyes in this category was greater with DEX implant 0.7 mg (from 94.5% at baseline to 60.2%) and DEX implant 0.35 mg (from 94.8% to 58.7%) than with sham (from 95.9% to 71.6%)" and "the 10th percentile of time to two-step improvement in diabetic retinopathy severity was ?24 and ?13 months for the DEX implant 0.7 and 0.35 mg treatment groups versus ?24 months for sham". Do the authors imply that the 0.35 mg DEX implant is as efficacious as the 0.7 mg implant or does it suggest better sustained metabolic control in the patients receiving the 0.35 mg implant? Moreover, since systemic hypertension is a risk factor for the development and progression of both diabetic retinopathy and DME, and hyperlipidemia increases the risk of leakage and exudative deposits in the macula [5], blood pressure and lipid profile should have been recorded at baseline and at subsequent visits to assess whether improvement in macular edema was as a result of strict systemic control or as a result of the implant itself. Lastly, since steroids exacerbate cataractous changes, it would be interesting to know the lens status in the three groups at final follow up. References 1. Danis RP, Sadda S, Li XY, et al. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3- year phase III trials. Br J Ophthalmol 2016;100:796-801. 2. Chhablani J, Bansal P, Veritti D, et al. Dexamethasone implant in diabetic macular edema in real-life situations. Eye 2016;30:426-430. 3. Zhang J, Ma J, Zhou N, Zhang B, An J. Insulin Use and Risk of Diabetic Macular Edema in Diabetes Mellitus: A Systemic Review and Meta-Analysis of Observational Studies. Medical Science Monitor?: International Medical Journal of Experimental and Clinical Research. 2015;21:929-936. 4. Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med 2012;172:1005-1011. 5. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002; 47(suppl 2): S253-S262.

  Conflict of Interest:

  None declared

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