COMPARATIVE EFFICACY OF INTRAVITREAL RANIBIZUMAB MONOTHERAPY WITH COMBINED INTRAVITREAL RANIBIZUMAB AND LASER PHOTOCOAGULATION THERAPY IN THE MANAGEMENT OF DIABETIC MACULAR EDEMA.

Abstract

given anti-VEGF agents in combination with MPC and those 30-31 given anti-VEGF agents alone . In our present study, we have compared the efficacy of intravitreal (anti-VEGF) injection Ranibizumab versus a combination therapy of injection Ranibizumab and laser in the treatment of DME in Type 2 non-proliferative diabetic retinopathy (NPDR) patients, so as to find out the best therapy for DME in a developing country like India, where repeated intravitreal injections of ranibizumab will certainly create a financial constrain. A Pilot studies with intravitreal Ranibizumab have also shown decrease in mean retinal thickness and improved vision in patients with DME. In three well designed, phase II or III trials 32 33 34 (RESOLVE , RIDE and RISE , READ 2 ) 1-2 year treatments with Ranibizumab were found to be more effective than sham or focal/grid laser therapy in improving best corrected visual acuity(BCVA) and reducing macular thickness in patients with visual impairment associated with DME. Along with these studies, two other well designed phase III trials 35 36 (RESTORE and DRCR.net ) showed that one year of treatment with Ranibizumab as an adjunct to laser therapy showed improvement at the first follow-up visits in these studies, and were associated with gains in vision related quality of life. Repeated intravitreal injections of this drug was used for this study. MATERIALS AND METHODSA: STUDY AREA This study was done at the Regional Inst i tute of Ophthalmology, Medical College and Hospital, Kolkata. The subjects belong to various districts of West Bengal. STUDY POPULATION Patients with Type 2 diabetes mellitus, who had diminution of vision only due to Nonproliferative diabetic retinopathy (NPDR) with diabetic macular oedema (DME) and not due to ischemic diabetic maculopathy, were randomly selected from o u t p a t i e n t d e p a r t m e n t o f R e g i o n a l I n s t i t u t e o f Ophthalmology, Kolkata. Further, patients with macular oedema≥350μm, found within central (1 mm diameter) subfield area in SD-OCT were involved in this study. Evaluation and management of all the cases were performed at the Retina Research Clinic of the Regional Institute of Ophthalmology, Kolkata. INCLUSION CRITERIA: 1. Patients having non -ischemic, non -proliferative diabetic retinopathy with macular oedema (≥350 um), found within central (1 mm diameter) subfield area in SD-OCT, all diagnosed and well controlled Type 2 Diabetes Mellitus, only newly diagnosed cases of NPDR with DME, not received any f orm of t reatment ( f ocal/gr id laser or in ject ion Ranibizumab/any form of intravitreal anti VEGF or intravitreal triamcinolone injection /any form of intravitreal steroid injection) in the past, including posterior sub Tenon steroid injection. EXCLUSION CRITERIA: Type 1 diabetes mellitus, Patients suffering from uncontrolled hypertension, thyroid eye disease, pregnancy, uncontrolled hypercholesteremia, anemia, renal disease or having some other systemic disease, which may affect the retinal thickness as judged by the treating ophthalmologist. STUDY DESIGN: An open label, randomized, parallel group, comparative trial. SAMPLE SIZE: 60 newly diagnosed eyes of patients of NPDR with macular oedema ≥350μm. A sample size of 30 in each of the two groups was selected. SAMPLE DESIGN: A computergenerated randomization schedule was followed. STUDY PARAMETERS: 1. The main outcome measures studied was the change in macular thickness within central subfield (1 mm area) in SDOCT, assessed in 3 follow-up visits in each group of Injection ranibizumab monotherapy and combined Injection ranibizumab and laser group, as evaluated by SD-OCT. 2. Scores for ETDRS visual acuity were measured at every followup. 3. Intraocular pressure (IOP) was measured by Goldmann Applanation Tonometer at the start and at the end of the study and also recorded when felt necessary. 4. Dilated fundus examination by slit lamp biomicroscopy with +90 dioptres and peripheral retinal examination with indirect ophthalmoscopy was performed in both eyes at every follow up and also when felt necessary. 5. Fluorescein angiography was performed to rule out ischemic diabetic retinopathy and proliferative diabetic retinopathy at the start of the patient enrollment. SD-OCT technique: After appropriate pupillary dilatation using Phenylephrine 5% +tropicamide 0.8% eye drops, the patient was seated comfortably on a chair in front of the device, in a dimly lit room, asked to place their chin on the chin rest, and to look at the centre of the green target, and not at the moving light inside the imaging aperture. The OCT volume scan was performed on a 20×20 degree cube with 49 raster lines, each containing 1064 pixels, separated by 120 μ. The high acquisition speed of 40,000 Ascans/ second avoids artifacts from micro saccades and improves image definition. STUDY TECHNIQUE: This prospective, randomized clinical study was done on 60 eyes of patients having NPDR with macular oedema ≥350μm in the central subfield (central 1 mm area) as per SD-OCT. Patients enrolled for this study had to undergo tests like FBS, PPBS, Hba1c, urea, creatinine, complete blood count, lipid profile , blood pressure checkup and cardiological fitness. Then the patients had to undergo visual acuity tests (ETDRS chart), Slit lamp examination, dilated fundus examination with direct and indirect ophthalmoscope including slit-lamp biomicroscopy with +90D, applanation tonometry, fluorescein fundus angiography (FFA) and spectral domain OCT (macular thickness mapping). Patients were randomized either in the Injection ranibizumab monotherapy group or in the combined group of Injection ranibizumab with modified grid laser. Both groups received monthly consecutive 3 intravitreal injections of Ranibizumab 0.5 mg initially, followed by which one group received focal/grid laser rd photocoagulation within 7-10 days, after the 3 injection, while another group was treated by repeated intravitreal administration of Injection Ranibizumab, when warranted until the end of 6 months. PROCEDURE: Intravitreal Ranibizumab injection: After taking written consent from the patient, six days prior to procedure patient was asked to instill eye drop Moxifloxacin ( 0.5%) 4 times/ day in the affected eye. On the day of procedure, the affected eye was dilated with combined topical preparation of Tropicamide (0.8%) and Phenylephrine hydrochloride (5%) eye drop. Then the eye is anesthesized with 0.5% topical proparacaine hydrochloride 2-3 minutes prior to injection. The eyelid and skin was cleaned with 10% Povidoneiodine and one drop of 5% Povidone –iodine was kept in the conjunctival sac for 3 minutes and then thoroughly washed with balanced salt solution and properly draped. Then 0.5 ml (0.5mg) of injection Ranibizumab will be loaded into an insulin syringe (30 gauges). After separating the lids with a 38 www.worldwidejournals.com PARIPEX INDIAN JOURNAL F RESEARCH | O March 202 Volume 10 | Issue 03 | 1 | PRINT ISSN No. 2250 1991 | DOI : 10.36106/paripex PARIPEX INDIAN JOURNAL F RESEARCH | O March 202 Volume 10 | Issue 03 | 1 | PRINT ISSN No. 2250 1991 | DOI : 10.36106/paripex wire speculum, 0.05 ml of Ranibizumab will be injected into the vitreous cavity through the inferiortemporal pars plana, 3.5 – 4 mm away from the limbus. Tamponade was applied at the site of injection with a swab stick for 2-3 mins. Topical antibiotic drop will be instilled after the injection. Patient was asked to remove the eyepad after 2 hours and also asked to instill eye drop Moxifloxacin (0.5%) 4 times/ day and antiglaucoma medication for 7 days. The intravitreal injection was given for 3 consecutive months initially, and if macular oedema persisted as assessed by SD-OCT, it was followed up by further additional doses of injection Ranibizumab until the th 6 month, in one group of patients. All the injections were given by a single surgeon. Intra-ocular pressure checkup and indirect ophthalmoscopy with scleral depression was performed after each intravitreal injection. Combined therapy: Here, patients will be given intravitreal Ranibizumab injection first for 3 consecutive months. Then if rd macular edema still persists, as assessed by SD-OCT, the 3 dose of intravitreal ranibizumab will be followed by a rd modified grid laser after 7-10 days of the 3 injection th Ranibizumab, and the final follow up visit will be done at 6 month. All patients in both procedures were followed up on all the st first post-operative days, and then 1 week after the 1 Injection Ranibizumab (First follow-up), 1 week after 2nd Injection Ranibizumab (Second follow-up) and then at 6 rd months after 3 Injection Ranibizumab+ grid laser at 7-10 days or after 3rd Injection Modified grid laser technique employs primarily grid treatment to areas of diffuse leakage with occasional focal treatment of focal leakage located either within or outside the areas of diffuse edema. Laser machine is adjusted with retinal spot size of 50-100 μm, duration of 0.1 seconds with light intensity to obtain gentle whitening. Laser spots are applied one burn width apart staying 500μm away from the foveal centre and the disc margin to up to 3000 μm from the macular centre excluding the area of papillomacular bundles. Foveal avascular zone is fastidiously avoided to p reve n t c e n t ra l s c o t o m a s . M o d i f i e d g r i d l a s e r photocoagulation is performed in 2-3 rows. Ranibizumab+ additional monthly Injections Ranibizumab, if needed until 6 months (3rd Follow up). Best corrected visual acuity (BCVA) was assessed with ETDRS chart at each visit and macular edema was evaluated with Spectral domain Optical Coherence Tomography (Central subfield) at the end rd of 1st ,2nd and 3 follow-ups. Any complications following the procedure were managed accordingly. Modified grid laser technique employs primarily grid treatment to areas of diffuse leakage with occasional focal treatment of focal leakage located either within or outsi