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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 16  |  Issue : 2  |  Page : 77-83

Short-term results of intravitreal ranibizumab injection in eyes with diabetic macular edema


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

Date of Submission21-Dec-2014
Date of Acceptance21-Mar-2015
Date of Web Publication28-Oct-2015

Correspondence Address:
Hesham S Swelem
Department of Ophthalmology, Faculty of Medicine, University of Alexandria, Al-Messalah, Alexandria 21521
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-9173.168536

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  Abstract 

Purpose
The aim of the study was to investigate the 1-week and 1-month effects of intravitreal injection of ranibizumab on central macular thickness (CMT) and visual acuity (VA) in patients with diabetic macular edema (DME).
Patients and methods
In this nonrandomized clinical study, 71 eyes of 62 patients with DME received intravitreal ranibizumab. VA and macular edema were assessed preoperatively and at 1 week and 1 month after injection. Eyes were subgrouped by spectral domain optical coherence tomography (SD-OCT) findings into spongiform edema, cystoid, serous retinal detachment, and tractional.
Results
Overall, the mean preinjection CMT was 432.0 ± 144.0 μm (range 202.0-846.0 μm); at 1 week it was 369.0 ± 99.33 μm (range 198.0-656.0 μm) with 11.54% improvement (P < 0.001), and at 1 month it was 341.0 ± 88.66 μm (range 191.0-608.0 μm) with 17.96% improvement (P < 0.001). Thirteen eyes with spongiform edema had a significant decrease in CMT (298-285-272 μm) (P = 0.001), yet had nonsignificant vision improvement. CMT decreased significantly in 42 eyes with cystoid edema (439-358-332 μm) (P < 0.001) and in 14 eyes with serous retinal detachment (476-447-386 μm) (P = 0.002). VA significantly improved in the latter two groups. Two eyes with tractional element showed no significant change in CMT and a significant drop in vision.
Conclusion
Intravitreal ranibizumab is effective in improving VA and decreasing macular edema after 1 week and 1 month after injection; except in eyes with tractional element, which can worsen. Eyes with cystoid edema or serous detachment exhibit significant improvements in both VA and CMT, whereas those with spongiform thickening show significant decrease in CMT without concomitant visual improvement. Therefore, patients could be counseled about the short-term changes in vision and macular edema depending on their SD-OCT-based subtype of DME.

Keywords: diabetes, macular thickness, ranibizumab


How to cite this article:
Sharaf A, Nabawi KS, Shalaby TM, Swelem HS. Short-term results of intravitreal ranibizumab injection in eyes with diabetic macular edema. Delta J Ophthalmol 2015;16:77-83

How to cite this URL:
Sharaf A, Nabawi KS, Shalaby TM, Swelem HS. Short-term results of intravitreal ranibizumab injection in eyes with diabetic macular edema. Delta J Ophthalmol [serial online] 2015 [cited 2021 Dec 3];16:77-83. Available from: http://www.djo.eg.net/text.asp?2015/16/2/77/168536


  Introduction Top


Diabetic retinopathy (DR) is one of the most common ocular complications of diabetes mellitus (DM) and its prevalence is higher in type I diabetic patients than in those with type II disease [1],[2] . It affects both the quality of life and the economic status of both the individual and the society [3],[4] . Macular edema is the major cause of visual loss in patients with DR. The incidence of diabetic macular edema (DME) after 10 years of follow-up has been reported to be 20.1% in type I diabetes, 25.4% in type II insulin-dependent diabetes, and 13.9% in type II non-insulin-dependent diabetes [5] . In the Early Treatment Diabetic Retinopathy Study (ETDRS), the 3-year risk of moderate visual loss [a doubling of the initial visual angle, e.g. 20/30 to 20/60, or a decrease of three lines or more on a logarithmic visual acuity (VA) chart] was 32% [6] . Optical coherence tomography (OCT) is a modern imaging technique for noninvasive and noncontact in-vivo examination of the retina and the vitreoretinal interface [7],[8],[9] . It is a valuable method for quantifying treatment effects after laser photocoagulation, vitrectomy, or intravitreal injection of steroids and antivascular endothelial growth factor (anti-VEGF). The high reproducibility of retinal thickness measurements allows it to be used for longitudinal objective monitoring of treatment efficacy. A change in macular thickness of more than 10% of the baseline measurement has been considered as significant and not due to variability of the method [10],[11] .

Currently there are three VEGF inhibitors available in clinical practice: (i) pegaptanib (Macugen; Pfizer, New York City, New York, USA); (ii) bevacizumab (Avastin; Genentech); and (iii) ranibizumab (Lucentis; Novartis). Ranibizumab is a recombinant humanized IgG1 k isotype monoclonal antibody fragment designed for intraocular use. It is indicated in the treatment of macular edema after retinal vein occlusion, wet age-related macular degeneration, and DME [12] . Ranibizumab binds to the receptor binding site of the active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells. This reduces endothelial cell proliferation, vascular leakage, and new blood vessel formation. Ranibizumab is administered intravitreally using a half-inch 30-G needle to administer 0.3-0.5 mg once per month. Following administration, ranibizumab reaches a peak vitreous concentration after 6 h. There is rapid distribution of the drug from the vitreous into either the retina or the anterior chamber, and the concentration in the retina is around one-third of that in the vitreous. The vitreous elimination half-life of ranibizumab is ~9 days, through an unknown mechanism of metabolism [12],[13] .

The aim of this work was to study the short-term effects of intravitreal ranibizumab injections in eyes with DME as regards VA and macular thickness up to 1 month after injection.


  Patients and methods Top


This prospective nonrandomized interventional clinical study included 71 eyes of 62 patients with DME who were recruited from the Ophthalmology Outpatient Clinic at Alexandria Main University Hospital from January 2013 to August 2013. Consent was taken from all participants. Patients were included if they had DME evidenced by slit lamp biomicroscopy, fluorescein angiography, and OCT.

Exclusion criteria were as follows:

  1. The presence of coexistent macular pathology such as age-related macular degeneration, central or branch retinal vein occlusion, uveitic macular disease, or trauma.
  2. Previous intraocular surgery (as cataract, vitrectomy) within the past 6 months.
  3. Previous intravitreal injections within the past 6 months.
  4. Previous laser treatment with panretinal photocoagulation or grid laser within the past 6 months.


Preoperative assessment included the following:

  1. History taking, type and duration of DM, hypertension, and ischemic heart disease.
  2. Best-corrected visual acuity (BCVA), converted to logMAR VA for statistical purposes.
  3. Slit lamp examination.
  4. Fundus examination through slit lamp biomicroscopy.
  5. OCT for assessment of central macular thickness (CMT) (Heidelberg Spectralis; Heidelberg Engineering, Carisbad, California, USA). Imaging was performed, after mydriasis, with the patient seated and the forehead resting on the forehead rest and the chin on the chin rest. During the examination, the patient looked into the imaging aperture and was asked to fixate the target against a dark background. The fast scan macular protocol with horizontal scanning at 9 frames/s was used.
Surgical procedure

With the patient lying supine on the operating table, and after eyelid disinfection (10% povidone iodine) and draping, a wire speculum that gives maximum exposure to the globe was applied. Topical anesthesia using 0.4% benoxinate hydrochloride eyedrops (EPICO, 10th of Ramadan, Egypt) was instilled preoperatively 5 min before the procedure. The patient was asked to look nasally and slightly upward to expose the inferotemporal quadrant of the sclera. Using a tuberculin syringe needle inserted 3.5-4.0 mm posterior to the limbus into the midvitreous cavity, avoiding the horizontal meridian and aiming toward the center of the globe, a volume of about 0.03 ml was delivered. Intravitreal injection of ~0.3 mg ranibizumab corresponding to an injection volume of ~0.03 ml was given in most cases, as a vial was usually divided between three consecutive cases. Ranibizumab has been developed by Genentech and is marketed in the USA by Genentech (San Fransisco, California) and elsewhere by Novartis (Basel, Switzerland) under the brand name Lucentis. Gentle pressure on the site of the injection was applied using a Merocel (Medtronic, Minneapolis, USA) sponge after removal of the syringe. The lid speculum was removed carefully and an eyepatch was placed.

Postoperative assessment

Follow-up was performed in the first week and first month postoperatively and included the following:

  1. BCVA.
  2. OCT for assessment of CMT to compare the preoperative macular thickness images with the 1-week and 1-month postinjection CMT images.
Statistical analysis

Data were fed into a computer and analyzed using IBM SPSS software package (version 20.0; SPSS Inc., Chicago, Illinois, USA). Qualitative data were expressed using number and percentage and quantitative data were described using mean, SD, median, and minimum and maximum values. The distributions of quantitative variables were tested for normality using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the D'Agstino test; histograms and QQ plots were used for vision results. If normal data distribution was revealed, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For abnormally distributed data, the Kruskal-Wallis test was used to compare between different groups, and for comparing between the different periods the Wilcoxon signed-rank test was applied. Significance test results were quoted as two-tailed probabilities. Significance of the obtained results was judged at the 5% level, where a P value of less than 0.05 was taken as significant.


  Results Top


Seventy-one eyes of 62 patients were examined clinically and they underwent Spectralis spectral domain (SD)-OCT testing and measurement of macular thickness. All of them received intravitreal ranibizumab injection for their DME. There were 38 right eyes and 33 left eyes. Seventeen patients were male and 45 were female. Their mean age was 57.17 ± 8.56 years (range 20-75 years) [Table 1]. [Table 2] shows the distribution of the studied cases according to the type and duration of DM. This comprised 43 patients with insulin-dependent DM and 19 non-insulin-dependent patients. The mean duration of diabetes in all patients was 14.17 ± 5.34 years (range 4-30 years). Thirty-eight patients had other comorbidities with DM [Table 3].
Table 1 Distribution of studied cases according to demographic data

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Table 2 Distribution of the cases according to diabetic state

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Table 3 Distribution of studied cases according to other comorbidities

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[Table 4] shows the logMAR BCVA. Mean preoperative VA was 1.0 ± 0.38 (range 0.22-2.08), and after 1 week it was 0.91 ± 0.35 (range 0.22-2.08) with 6.65% improvement. After 1 month it was 0.80 ± 0.39 (range 0.22-2.30) with 19.31% improvement from baseline values. The improvement in VA from baseline at 1 week and at 1 month after injection was statistically significant (P < 0.05).
Table 4 Distribution of studied eyes according to logMAR best-corrected visual acuity

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The mean preoperative CMT as per OCT was 432.0 ± 144.0 μm (range 202.0-846.0 μm). After 1 week the mean CMT was 369.0 ± 99.33 μm (range 198.0-656.0 μm) with 11.54% improvement, and after 1 month it was 341.0 ± 88.66 μm (range 191.0-608.0 μm) with 17.96% improvement [Table 5]. The decrease in CMT at 1 week and at 1 month compared with baseline values was statistically significant (P < 0.05).
Table 5 Distribution of studied eyes according to central macular thickness (u)

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[Table 6] shows the incidence of the different OCT subtypes of macular edema in the study patients. Forty-two (59.2%) eyes had cystoid edema. Fourteen (19.7%) eyes showed serous retinal detachment. Spongiform edema was present in 13 (18.3%) eyes and a tractional epiretinal membrane was present in two (2.8%) eyes.
Table 6 Optical coherence tomography morphology of macular edema in the studied eyes

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The longitudinal change of the CMT and of the BCVA, according to the OCT subtype of macular edema, over 1 month is shown in [Table 7] and [Table 8], respectively. Notably, all subtypes of macular edema showed a statistically significant decrease in CMT at both 1 week and 1 month after injection except the cases with a tractional component in which there was no significant change in thickness after injection [Table 7]. VA improved significantly 1 month after injection in cases with cystoid edema and in those with serous detachment (P < 0.05). There was no significant change in vision in patients with spongiform edema, whereas the two eyes exhibiting traction actually experienced a drop in VA 1 month after intavitreal ranbizumab injection compared with preinjection acuity [Table 8].
Table 7 Distribution of central macular thickness in different types of macular edema

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Table 8 Distribution of logMAR best-corrected visual acuity in different types of macular edema

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  Discussion Top


DME is a manifestation of DR and is the leading cause of moderate visual loss in diabetics. Given that most eyes with DME that are treated with laser photocoagulation do not show an improvement in VA, there has been an interest in other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and the use of intravitreal corticosteroids. The use of antibodies targeted at VEGF is another modality that has generated considerable interest and investigation [13],[14] . Ranibizumab binds to the receptor binding site of the active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells. This reduces endothelial cell proliferation, vascular leakage, and new blood vessel formation.

The aim of the current study was to evaluate the short-term effect of ranibizumab on BCVA and CMT in DME. It demonstrated the rapid efficacy of ranibizumab in patients with DME in decreasing CMT and improving BCVA over 1 month after injection. Patients with DME prepared for intravitreal ranibizumab should anticipate VA and macular thickness changes in the short term. No previous studies addressed the short-term effects of intravitreal ranibizumab on VA and CMT based on SD-OCT grouping. Seventy-one eyes of 62 patients with DME at Alexandria Main University Hospital were studied; 38 were right eyes and 33 were left eyes. There were 17 male and 45 female patients. Their mean age was 57.17 ± 8.56 years. Twenty-two (35%) patients had hypertension, and nine (14.5%) had ischemic heart. The cystic type was the most common edema type (59.2% of cases). The percentage improvement of CMT in all patients was 17.96%, and BCVA improved by 19.31%. The preinjection mean CMT of all patients was 432.0 ± 144.0 μm, which significantly improved by 17.96% at 1 month to 341.0 ± 88.66 μm. The preinjection mean BCVA was 1.0 ± 0.38, with significant improvement by 19.31% at 1 month to 0.80 ± 0.39. Eyes with spongiform edema had a significant decrease in CMT yet had nonsignificant vision improvement. CMT decreased significantly in eyes with cystoid or serous retinal detachment. VA significantly improved in the latter two groups. Those with tractional element showed no significant change in CMT and a significant drop in vision. Thus, ranibizumab had a big effect on all types of DME except those with a tractional component.

The results of the current study are, in general, in agreement with a number of key studies assessing intravitreal ranibizumab in the treatment of DME. These include the RISE and RIDE studies, the RESOLVE and READ-2 studies, and the RESTORE trial. The RISE and RIDE trials compared monthly ranibizumab versus placebo. Laser therapy was offered as a potential rescue therapy. A significantly larger percentage of the ranibizumab arm had a 15-letter gain in acuity compared with placebo, and larger reductions in DME [15] .

The DRCR.net conducted a large, multicenter, randomized clinical trial showing that intravitreal injections of ranibizumab with prompt or deferred laser is more effective than prompt laser treatment alone for DME [16] . In this study, 854 study eyes were randomized to sham injection with prompt laser, to 0.5 mg ranibizumab with prompt laser, to 0.5 mg ranibizumab with deferred (≥24 weeks) laser, or to 4 mg triamcinolone with prompt laser. Sham or ranibizumab injections were given every 4 weeks up to week 12. In the 2-year follow-up of this study, 29% of patients receiving ranibizumab plus prompt laser and 28% of patients receiving ranibizumab plus deferred laser had 15 or more letters of improvement, compared with 18% of patients in the prompt laser-only group and 22% of patients in the triamcinolone plus prompt laser group. Overall, this study clearly demonstrated that ranibizumab therapy (alone or in combination with laser) is superior to laser monotherapy [16] .

READ-2 trial

The first landmark study to demonstrate the efficacy of ranibizumab monotherapy was the READ-2 study. This prospective, multicenter trial randomized 126 patients to receive ranibizumab, ranibizumab and laser, or laser alone. The ranibizumab group received 0.5 mg at baseline and at months 1, 3, and 5. The laser group received laser photocoagulation at baseline and at month 3 if needed, and the combination group received 0.5 mg ranibizumab and laser at baseline and at month 3. The primary endpoint was 6 months, where the mean number of ETDRS letters gained in the ranibizumab group was 7.24 letters, in the combination group was 3.80 letters, and in the laser-alone group there was a mean reduction of 0.43 ETDRS letters. In the long-term follow-up at 24 months, the laser group had an increase of 5.1 letters; the increase in the ranibizumab group (7.7 letters) and the combination group (6.8 letters) was higher, although not significantly so. At the 24-month point, 24% of patients in the ranibizumab monotherapy group gained 15 or more ETDRS letters compared with 18% of laser monotherapy patients and 26% of combination therapy patients. This trial complemented the DRCR.net trial, as it demonstrated that long-term improvements in VA could be achieved with ranibizumab monotherapy [17] .

Restore

The DRCR.net and READ studies examined the therapeutic potential of ranibizumab for the treatment of DME in the USA. It was anticipated that the efficacy of ranibizumab could be extrapolated to populations outside of the USA; this assumption has been supported by several international clinical trials. The RESTORE study group examined patients from 10 European countries. The investigators found that at the primary endpoint (12 months) the average gain in ETDRS letters in the ranibizumab monotherapy group was 6.1, in the combination group was 5.9, and in the laser monotherapy group was 0.8. At the 12-month endpoint, the percentage of patients who gained 15 or more letters was 26, 27, and 9 for the ranibizumab monotherapy, combination therapy, and laser monotherapy groups, respectively. The results provided good evidence that long-term treatment with ranibizumab is effective for the treatment of DME and showed ranibizumab to be better than laser monotherapy both in OCT findings and in VA [18] .

The wealth of data from the clinical trials described here strongly suggest that ranibizumab injections are beneficial for the treatment of DME. However, it could be seen that they did not address the 1-week and 1-month effect of a single ranibizumab injection on vision and edema, which the current trial assessed. This could be beneficial in telling patients what to expect in the short term. Thus, although the results seem to be expected and give additional proof of the beneficial effect of intravitreal injection of ranibizumab in eyes with DME, we may have in our hands numbers and percentages regarding CMT and VA changes at the end of the first follow-up visit. An almost 20% improvement of VA may be an acceptable reward for patients with cystic and subretinal fluid (SRF) types of DME to continue their journey for further intravitreal injection (this is equivalent to an approximate decrease in CMT of 20%). At 1 month after injection, eyes with cystic and subretinal fluid subtypes had the highest visual gain, whereas vision dropped in the tractional subtype. It is advised that this latter group not receive injections for fear of increasing retinal traction [19] . Patients with spongiform DME seemed to have a nonsignificant improvement of their VA at 1 month. A probable explanation could be less disruption of their inner segment/outer segment (IS/OS) junction (that was not studied in patients) in comparison with eyes with cystic and/or SRF DME who have disruption of their outer retinal layers.

In conclusion, the current study demonstrated the efficacy of intravitreal ranibizumab in improving VA and decreasing macular edema after 1 week and 1 month after injection, except in eyes with tractional element, which can worsen. The latter category of patients should be advised against intravitreal injections. Eyes with cystoid edema or serous detachment exhibited significant improvements in both VA and CMT, whereas those with spongiform thickening showed significant decrease in CMT without concomitant visual improvement. Thus, patients could be counseled about the short-term changes in vision and macular edema depending on their SD-OCT-based subtype of DME.


  Acknowledgements Top


Conflicts of interest

None declared.

 
  References Top

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Sharma S, Oliver-Fernandez O, Liu W, Buchholz P, Walt J. The impact of diabetic retinopathy on health-related quality of life. Curr Opin Ophthalmol 2005; 16:155-159.  Back to cited text no. 3
    
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Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, et al. READ-2 Study Group Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2009; 116:2175-2181.  Back to cited text no. 13
    
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Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. RISE and RIDE Research Group Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012; 119:789-801.  Back to cited text no. 15
    
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Rizzo S, Genovesi-Ebert F, Di Bartolo E, Vento A, Miniaci S, Williams G Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol 2008; 246:837-842.  Back to cited text no. 19
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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