Monthly Ranibizumab Research Articles

Retinal Fluid and Thickness Fluctuations in Archway Trial for Port Delivery System with Ranibizumab versus Monthly Ranibizumab Injections

PurposeTo determine proportion of eyes with neovascular age-related macular degeneration (nAMD) with retinal fluid and/or central subfield thickness (CST) fluctuations and evaluate their impact on best-corrected visual acuity (BCVA) in eyes treated with the Port Delivery System with ranibizumab (PDS) versus monthly intravitreal ranibizumab injections. DesignPost-hoc analyses of phase 3 Archway trial (NCT03677934). ParticipantsAdults with nAMD responsive to anti-vascular endothelial growth factor therapy. Intervention418 patients randomized 3:2 to the PDS (100 mg/mL) with refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab (0.5 mg) for 96 weeks. OutcomesProportion of eyes in each treatment arm with subretinal and/or intraretinal fluid (SRF/IRF) overall and in central 1-mm; BCVA changes from baseline by treatment arm and fluid presence/location; proportion of eyes with CST fluctuations from baseline to week 48, week 48 to 96, and baseline to week 96; effects of CST fluctuations on BCVA. Results415 eyes were assessed. In the PDS versus monthly ranibizumab arm, proportion of eyes with SRF/IRF, central SRF, and central IRF were 47.6% versus 50.9%, 29.0% versus 19.2%, and 11.7% versus 12.6% at baseline, and 57.8% versus 56.1%, 21.6% versus 14.8%, and 7.0% versus 8.4% at week 96. BCVA changes from baseline to week 96 were –1.1 letters with the PDS versus –1.4 with monthly ranibizumab in eyes with SRF/IRF, and –1.9 versus –1.8 in eyes with central SRF. In eyes with central IRF, BCVA changes from baseline to week 96 were –2.1 with the PDS versus –6.9 with monthly ranibizumab, respectively (mean BCVA at 96 weeks 68.9 [20/40] versus 64.6 [20/50]). CST fluctuations occurred in 32.1% and 29.7% of PDS versus monthly ranibizumab eyes; corresponding BCVA changes from baseline to week 96 were –2.5 versus –2.6 (mean BCVA at 96 weeks 72.7 [20/35] versus 71.5 [20/38]). ConclusionsPDS Q24W maintained BCVA to 96 weeks regardless of SRF/IRF, central SRF, central IRF, or CST fluctuations, comparable with monthly ranibizumab, thus supporting the use of the PDS in stabilizing retinal anatomy without the need for monthly treatment in patients with nAMD.

Interim Results of the Phase III Portal Extension Trial of the Port Delivery System with Ranibizumab in Neovascular Age-Related Macular Degeneration

ObjectiveThe Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration (nAMD). Portal (NCT03683251) is evaluating long-term safety and tolerability of the PDS in patients with nAMD who completed the phase II Ladder (NCT02510794) or phase III Archway (NCT03677934) trials. DesignMulticenter, nonrandomized, open-label, extension clinical trial. ParticipantsAll-PDS safety population (N = 555) comprises patients enrolled in Portal who completed Ladder or Archway. Due to data availability, efficacy population comprises Ladder-to-Portal patients only: patients who previously received PDS 10, 40, or 100 mg/ml pro re nata (as-needed [PRN]; n = 58, 62, 59, respectively) or monthly intravitreal ranibizumab 0.5-mg injections (monthly ranibizumab; n = 41) in Ladder and subsequently enrolled in Portal. MethodsLadder patients received PDS refill-exchanges PRN or monthly ranibizumab. Archway patients received PDS 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or monthly ranibizumab. Once enrolled in Portal, all patients receive PDS Q24W from day 1. Main Outcome MeasuresOcular adverse events of special interest (AESIs); changes from baseline in best-corrected visual acuity (BCVA) and center point thickness (CPT); supplemental ranibizumab treatment between refill-exchange procedures; PDS Patient Preference Questionnaire results. ResultsIn the All-PDS safety population (mean follow-up, 111 weeks), 137 (24.7%) patients had ≥ 1 ocular AESI; most common were cataract (11.4%), vitreous hemorrhage (6.1%), conjunctival thickening (bleb)/filtering bleb leak (6.3%). Endophthalmitis occurred in 11 of 555 (2.0%) patients. For Ladder-to-Portal patients previously treated with PDS 100 mg/ml or monthly ranibizumab, BCVA remained stable from baseline to month 48; mean (95% confidence interval) changes from baseline were 0.1 (−6.6, 6.8; n = 31) and 2.3 (−9.4, 14.1; n = 15) letters, respectively; CPT remained stable through month 48. Approximately 95% of patients did not need supplemental treatment before each refill-exchange for > 2 years since Portal enrollment. Of Ladder-to-Portal previous monthly ranibizumab patients, 92% preferred the PDS over injections. ConclusionsInterim results from Portal suggest 4-year maintenance of visual/anatomic outcomes with PDS 100 mg/ml, with the PDS preferred to monthly injections. Long-term safety profile of the PDS is well characterized.

Comparison of Methods of Clinical Trial Emulation Utilizing Data From the Comparison of AMD Treatment Trial (CATT) and the IRIS® Registry

PurposeWe used exact matching and inverse propensity score weighting (IPSW) using real-world data (RWD) from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) to emulate the two pro re nata (prn) treatment arms from the Comparison of AMD Treatment Trial (CATT) and to compare the outcomes of the RWD arms to the two monthly treatment arms from the clinical trial. DesignRetrospective cohort study utilizing deidentified electronic health record registry data and patient-level deidentified clinical trial data SubjectsAll treatment-naive patient eyes with neovascular age-related macular degeneration treated with ranibizumab or bevacizumab only for one year from either the CATT or the IRIS Registry MethodsPatients were identified in the IRIS Registry between October 1, 2015 and December 31, 2019. After all non-imaging based inclusion and exclusion criteria from the CATT were applied, patient eyes receiving bevacizumab or ranibizumab only on a prn basis were identified as the eligible cohort. Exact matching and ISPW was applied based on age, gender, and baseline visual acuity. ResultsWe identified 427 eyes treated with ranibizumab prn and 771 eyes treated with bevacizumab prn. Using exact matching, 98% (n= 281) of CATT patient eyes in the bevacizumab monthly treatment arm and 87% (n=261) of CATT patient eyes in the ranibizumab monthly treatment arm were matched to a patient eye in the IRIS Registry. For the ranibizumab prn treatment arm, patient eyes generated using exact matching gained 1.9 letters and those generated using IPSW gained 2.8 letters (Exact Matching: 1.9 letters +/- 14.0 vs. IPSW: 2.8 letters +/- 15.0 letters, p=0.43). For the bevacizumab prn treatment arm, patient eyes generated using exact matching gained 2.4 letters and those generated using IPSW gained 2.1 letters (Exact Matching: 2.4 letters +/- 15.4 vs. IPSW: 2.1 letters +/- 16.0 letters, p=0.79). ConclusionsBoth exact matching and IPSW produced similar results in emulating the prn treatment arms of the CATT using IRIS Registry data and patient-level clinical trial data. Similar to prior real-world studies, the clinical outcomes were significantly worse in the IRIS Registry treatment arms compared to the clinical trial.

Changes in foveal avascular zone area and retinal vein diameter in patients with retinal vein occlusion detected by fundus fluorescein angiography.

To investigate changes in foveal avascular area (FAZ) and retinal vein diameter in patients with retinal vein occlusion (RVO) after intravitreal ranibizumab, and to analyze the correlation between ranibizumab therapy and visual gain. This retrospective study enrolled 95 eyes of 95 patients who had accepted three consecutive monthly ranibizumab injections, including 50 branch RVOs (BRVOs) and 45 central RVOs (CRVOs). BRVOs were divided into ischemia group (n = 32) and non-ischemia group (n = 18), and CRVOs also had ischemia group (n = 28) and non-ischemia group (n = 17). Comprehensive ophthalmic examinations were performed before the first injection and after 6, 12, and 24 months. The FAZ was manually circumscribed on early-phase images of fundus fluorescein angiography. Retinal vein diameters were measured on fundus photographs. After three injections, the FAZ area was significantly enlarged firstly and then reduced in all ischemic RVOs and the non-ischemic BRVOs (p < 0.05), while the retinal vein diameter was significantly reduced firstly and then increased in all groups except for unobstructed branch veins of non-ischemic BRVOs (p < 0.05). The correlation between the FAZ area and best corrected visual acuity was statistically significant in all CRVOs (non-ischemic, r = 0.372; ischemic, r = 0.286; p < 0.01) and ischemic BRVOs (r = 0.180, p < 0.05). Spearman's correlation analysis revealed that the retinal vein diameter was significantly correlated to the larger FAZ area in obstructed branch veins of ischemic BRVOs (r = -0.31, p < 0.01), inferior temporal branch veins of non-ischemic CRVOs (r = -0.461, p < 0.01) and ischemia CRVO groups (superior temporal branch vein, r = -0.226, p < 0.05; inferior temporal branch vein, r = -0.259, p < 0.01). After three consecutive monthly ranibizumab injections, the FAZ area was enlarged and retinal vein diameter reduced with gradual recovery to near baseline from 12 months. These results suggest that ranibizumab therapy can worsen macular ischemia and prevent visual gain in the short term. It has important significance for the treatment and prognosis of RVO, although the natural course of RVO may also affect ischemia and visual gain.

Analysis of ocular fluid in patients with ranibizumab-recalcitrant neovascular age-related macular degeneration who have serum anti-ranibizumab antibodies.

To evaluate whether anti-drug antibodies (ADAs) are present in the ocular fluid of patients with ranibizumab-recalcitrant neovascular age-related macular degeneration (nAMD). Two serum ADA-positive ranibizumab-recalcitrant patients and two serum ADA-negative controls were recruited from patients with nAMD treated with ranibizumab monotherapy. Recalcitrance was defined as persistent fluid after ≥6 monthly ranibizumab injections. Serum and aqueous humor ADAs were detected by enzyme-linked immunosorbent assay and immunoprecipitation, respectively. Two of 156 ranibizumab-treated patients were ADA-positive. The patients received six and 14 ranibizumab injections, respectively, up to 4 weeks prior to blood collection. The serum ADA concentration was estimated to be approximately 50,000 ng/mL. Neutralizing ADAs were confirmed in both samples. A specific band was detected by immunoprecipitation only in ADA-positive samples, consistent with the results of enzyme-linked immunosorbent assay. Based on an assessment of the degree of sensitivity of commercially available anti-ranibizumab antibodies, it was estimated that the immunoprecipitation method could detect ADA levels >30 ng. Nevertheless, ADAs were not detected in the aqueous humor of either the experimental or control group. In the aqueous humor, ADAs are either not present or are present at a lower concentration than that which can be detected by immunoprecipitation. This presumably reflects the fact that blood ADA is the product of systemic circulation clearance through anterior elimination of intravitreal ranibizumab. Based on our results, ADAs do not return to the eye in sufficient quantities to interfere with the action of ranibizumab in the vitreous cavity.

Topical bromfenac as adjunctive treatment with intravitreal ranibizumab for diabetic macular edema

PurposeTo determine the safety and efficacy of adding topical bromfenac 0.09% in the treatment of diabetic macular edema.MethodsSeventy patients (70 eyes) with center involved diabetic macular edema with macular thickness (300–500 μm) were included. Patients were divided randomly into two groups: 35 eyes in each group. Both groups were treated with intravitreal ranibizumab monthly for three consecutive months. Bromfenac 0.09% eye drops twice daily was added to the treatment of study group for six months from commencement of treatment. The efficacy of topical bromfenac was evaluated by comparing both groups through follow-up period as regards to visual acuity, central and average thickness and the need for re-injection.ResultsPatients treated with topical bromfenac in addition to intravitreal ranibizumab revealed significant improvement in visual acuity, more reduction in central and average macular thickness and less tendency to need reinjection compared to those treated with ranibizumab alone (p 0.013, p 0.010 and p 0.022, respectively). No side effects was encountered with the use of topical bromfenac.ConclusionTopical bromfenac 0.09% twice a day could enhance and sustain the efficacy of intravitreal ranibizumab in the treatment of diabetic macular edema without increasing the incidence of corneal side effects.

Clinical Characteristics and Long-term Outcomes in Diabetic Macular Edema Patients: With or without Additional Injection Following Ranibizumab Loading

PurposeTo investigate the baseline characteristics in patients with diabetic macular edema (DME) during 7 years according to the need for additional treatments after intravitreal ranibizumab (RBZ) loading injections.MethodsThe medical records of 32 patients treated with intravitreal RBZ loading for DME during 7 years were reviewed. After three-consecutive monthly RBZ injections, additional treatment was decided according to the patient’s response to RBZ loading. Based on whether the patients received treatment with or without additional injections, including intravitreal antivascular endothelial factor or steroid injection, they were divided into the “no add (NA)” or “add” groups, respectively. The baseline best-corrected visual acuity (BCVA), macular volume (MV), central subfoveal thickness, and other clinical factors were analyzed, and their 7-year changes were compared between the two groups.ResultsThe BCVA of the NA group was better than that of the add group at 2, 3, 5, and 7 years (year 2, 3, and 5; p < 0.01, respectively). Baseline MV was significantly smaller in the NA group than in the add group (10.72 ± 0.88 μm vs. 11.98 ± 1.64 μm, p = 0.008). The DME duration before treatment in the NA group was significantly shorter than in the add group (1.03 ± 0.98 years vs. 1.91 ± 1.33 years, p = 0.042). The proportion of patients with serous retinal detachment or cystic macular edema was significantly lower in the NA group than in the add group (35.3% vs. 73.3%, p = 0.042). The NA group had smaller MV until 2 years than the add group (year 1, p = 0.002; year 2, p = 0.006).ConclusionsThe DME patients without additional treatments during 7 years after the initial loading treatment had shorter duration of DME and diffuse retinal thickening morphologic type with lower MV at baseline, and better long-term visual prognosis.

Effect of less aggressive treatment on diabetic retinopathy severity scale scores: analyses of the RIDE and RISE open-label extension

ObjectiveTo evaluate factors associated with Diabetic Retinopathy Severity Scale (DRSS) changes with less frequent ranibizumab after induction therapy.Methods and analysisPost hoc analyses of RIDE/RISE and their open-label extension (OLE). Analyses...

Cost Analysis: Port Delivery System versus Monthly Ranibizumab for Wet Age-Related Macular Degeneration Treatment

A cost analysis of the Port Delivery System (PDS) versus monthly intravitreal ranibizumab (IVR) in the treatment of neovascular age-related macular degeneration (AMD) was performed based on the 96-week ARCHWAY trial results.

Prevalence and Progression of Macular Atrophy in Eyes with Neovascular Age-Related Macular Degeneration in the Phase 2 Ladder Trial of the Port Delivery System with Ranibizumab

To determine whether the rates of macular atrophy (MA) differ between eyes with neovascular age-related macular degeneration (nAMD) treated continuously with the Port Delivery System with ranibizumab (PDS) and those treated with ranibizumab given as a bolus intravitreal injection. A preplanned exploratory analysis of a phase 2, multicenter, randomized, active treatment-controlled, dose-ranging study. Patients diagnosed with nAMD within 9 months of screening who had received at least 2 previous intravitreal anti-vascular endothelial growth factor injections of any agent and were responsive to the treatment. Eyes were randomized (3:3:3:2) to treatment with either the PDS (filled with a customized formulation of ranibizumab at 10, 40, or 100 mg/ml and refilled pro re nata) or monthly intravitreal ranibizumab 0.5-mg injections. The prevalence, incidence, and progression of MA. The analysis population consisted of 220 eyes (58, 62, 59, and 41 eyes in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg injection arms, respectively). At study baseline, MA was observed in 14.5% (PDS 10-mg/ml), 11.5% (PDS 40-mg/ml), 13.6% (PDS 100-mg/ml), and 7.6% (monthly ranibizumab) of eyes. At the last assessment (mean, 22.1 months), the prevalence of MA had increased to 38.6% (PDS 10-mg/ml), 40.0% (PDS 40-mg/ml), 40.4% (PDS 100-mg/ml), and 45.7% (monthly ranibizumab). In patients without MA at baseline, a higher proportion of eyes in the monthly ranibizumab arm (40.6%) developed MA than in those in the PDS arms (28.6%, 32.1%, and 30.6% of eyes in the PDS 10-, 40-, and 100-mg/ml arms, respectively). The mean change in the area of MA from baseline to the last assessment for the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly ranibizumab arms was+2.46,+1.61,+1.09, and+1.15 mm2, respectively. At 9 months, for patients without MA at baseline, the difference in the incidence of MA between the PDS 100-mg/ml and monthly ranibizumab groups was-12% (95% confidence interval,-31% to 7%). In the phase 2 Ladder trial, there was no evidence of worse MA with the PDS compared with that with monthly intravitreal ranibizumab 0.5-mg injections. Larger trials focusing on MA are needed to confirm this finding.

Development of the Port Delivery System with ranibizumab for neovascular age-related macular degeneration.

This review provides background on the remaining unmet needs with antivascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (nAMD). We also discuss the developmental story of the Port Delivery System with ranibizumab (PDS; SUSVIMO, Genentech, Inc., South San Francisco, CA, USA). Real-world studies have shown that undertreatment is a major reason for continued vision loss in the anti-VEGF era. As a result, there is a need for long-acting anti-VEGF treatment options for patients with nAMD, diabetic macular edema, and other retinal diseases. The PDS is a solid state, refillable, intraocular long-acting drug delivery system that continuously delivers a customized formulation of ranibizumab into the vitreous for 6 months. In a phase 3 trial, the PDS showed equivalent visual acuity improvements with monthly ranibizumab injections in patients with nAMD and adverse events associated with the PDS were well understood and manageable. The PDS is the first US Food and Drug Administration-approved treatment for nAMD that provides continuous delivery of an anti-VEGF molecule. The PDS offers a unique drug delivery system that has the potential to serve as a platform to be used with other molecules in the future.

MiRNA Levels as a Biomarker for Anti-VEGF Response in Patients with Diabetic Macular Edema.

Background: The aim of this study was to investigate whether miRNA levels in the circulation could serve as a predictive biomarker for responsiveness to anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema. Methods: Whole blood samples were collected at baseline from 135 patients who were included in the BRDME study, a randomized controlled comparative trial of monthly bevacizumab or ranibizumab treatment for 6 months in patients with diabetic macular edema (Trialregister.nl, NTR3247). Best corrected visual acuity letter score (BCVA) and retinal central area thickness (CAT) were measured monthly during the 6-month follow-up. Levels of selected miRNAs were quantified. Results: Following linear regression analysis, the levels of four miRNAs were negatively associated with baseline CAT. Multivariable regression analysis confirmed this association for miR-181a. No associations with changes in CAT after 3 or 6 months of anti-VEGF treatment were found. In addition, no associations with miRNA levels with baseline BCVA or change in BCVA after 3 or 6 months of anti-VEGF treatment were found. Conclusions: Circulating miR-181a levels were negatively associated with CAT at baseline. However, no associations between miRNA levels and the response to anti-VEGF therapy were found.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration

To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). Primary end point was change in best-corrected visual acuity (BCVA) EarlyTreatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was+0.2 letters (standard error [SE], 0.5letters) in the PDS Q24W arm and+0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

Port delivery system: a novel drug delivery platform to treat retinal diseases

ABSTRACT Introduction Retinal disease treatment delivery is mostly limited to intravitreal injections and slow-release injectable implants due to structural barriers in the eye, and carry associated adverse effects and relatively high treatment burden. The Port Delivery System with ranibizumab (PDS) is a novel drug delivery device that is surgically implanted into the vitreous cavity and allows for continuous release of the anti-vascular endothelial growth factor (anti-VEGF) ranibizumab, eliminating the need for frequent intravitreal injections while maintaining therapeutic intraocular drug levels to control disease activity. Investigations of PDS are summarized in this review. Areas covered The most recent reported findings from preliminary studies and phase I–III trials are reviewed. We discuss the ramifications of these studies and the future potential for PDS in the treatment of retinal diseases. Expert opinion PDS is a novel drug delivery platform for the treatment of retinal diseases. Currently, the data from the PDS has shown promising efficacy and ability to substantially mitigate treatment burden while effectively generating visual and anatomic outcomes similar to those in patients receiving the standard monthly ranibizumab for neovascular age-related macular degeneration. Further studies are ongoing to investigate this novel drug delivery system in other disease states.

Short-Term Outcomes following “Switching” to Monthly Ranibizumab in Neovascular Age-Related Macular Degeneration Showing Insufficient Response to Bimonthly Aflibercept

Results CRT and logMAR VA were 349.62 ± 223.51 μm and 0.50 ± 0.23 at the baseline and 274.69 ± 148.77 μm and 0.46 ± 0.24, 311.54 ± 192.90 μm and 0.45 ± 0.20 at 1 month after the first and third ranibizumab injections, respectively. The CRT decrease during three ranibizumab injections was statistically significant (38.08 ± 69.52 μm, p=0.033). Change in VA was not statistically significant. The percentage of eyes with SRF was 100% at baseline and 53.8%, 76.9%, and 69.2% one month after each ranibizumab injections. The percentage of eyes with IRF was 38.5% at baseline and 23.1%, 23.1%, and 15.4%, respectively, after switching. Conclusion Switching to monthly ranibizumab in nAMD showing an insufficient response to bimonthly aflibercept led to immediate anatomical improvement. It can be considered in countries where the healthcare insurance system limits the minimum injection interval of aflibercept.

ANGIOGRAPHIC RISK FACTORS FOR RECURRENCE OF MACULAR EDEMA ASSOCIATED WITH BRANCH RETINAL VEIN OCCLUSION.

To examine angiographic risk factors for the recurrence of macular edema associated with branch retinal vein occlusion. We consecutively included 51 patients with treatment-naive branch retinal vein occlusion involving the macular area. Each eye initially received 3 monthly ranibizumab injections, with additional injections as necessary. At Month 3, we examined parafoveal vessel diameter indexes (VDI) in all sectors using optical coherence tomography angiography and determined the association with retinal thickness changes (Month 3-Month 5) and the number of ranibizumab injections during 12 months. Parafoveal VDIs in the affected, nasal, and temporal sectors at Month 3 were significantly associated with corresponding parafoveal thickening (P = 0.020, 0.010, and <0.001, respectively), and the parafoveal VDIs in the affected and temporal sectors were significantly associated with future foveal thickening (P = 0.037, and 0.026, respectively). Moreover, the parafoveal VDI in the temporal sector showed a significant association with the total required number of ranibizumab injections (P = 0.040). The parafoveal VDI may adequately represent the degree of congestion associated with branch retinal vein occlusion. Particularly, the VDI in the temporal sector may be a good predictor of future retinal thickening in the corresponding parafovea and the fovea and the number of ranibizumab injections.

Changes in Macular Microvascular Structure in Macular Edema Secondary to Branch Retinal Vein Occlusion Treated with Antivascular Endothelial Growth Factor for One Year.

Purpose To observe the changes in macular microvascular structure and the correlation between anatomy and visual function in patients with macular edema secondary to branch retinal vein occlusion (BRVO) treated with antivascular endothelial growth factor for one year. Methods This prospective study enrolled 39 patients (one eye per patient) who received intravitreal injections of ranibizumab for macular edema secondary to BRVO. All patients received a minimum of 3 initial monthly ranibizumab injections and criteria-driven pro re nata (PRN) dosing thereafter for visual acuity (VA) and central retinal thickness (CRT) stabilization. The follow-up period of this study was one year. The vascular density (VD) of the superficial retinal capillary plexus (SCP) and deep retinal capillary plexus (DCP), the foveal avascular zone (FAZ) area, the FAZ perimeter, the VD within a 300 μm wide ring surrounding the FAZ (FD-300), and the acircularity index (AI) were measured automatically by optical coherence tomography angiography (OCTA) at baseline, month 6, and month 12. Results Compared with those before treatment, the VD of the SCP significantly decreased 6 months after treatment (P < 0.05), while the area and perimeter of the FAZ increased significantly (P < 0.01). After 12 months of treatment, the area and perimeter of the FAZ increased significantly (P < 0.01). There was no significant difference in any parameters between 12 months and 6 months after treatment (P > 0.05). The change in BCVA was negatively correlated with the VD of the SCP at 12 months (P=0.0447, r = −0.3233). There was a relationship between the DBP and AI, and CRT was related to VD of DCP at baseline (P=0.028, 0.0209; r = 0.383, −0.384). The PERIM and AI at 12 months were significantly associated with the recurrence of macular edema, and the changes in vascular density in the SCP and PERIM were significantly associated with the number of injections within 12 months (P < 0.05). Conclusions One year after ranibizumab treatment, the area and perimeter of the FAZ were enlarged, while the VD of the SCP and DCP remained stable, which indicated that ranibizumab treatment did not improve macular blood supply and macular ischemia in BRVO patients.

Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab

BackgroundDespite the good outcomes achieved with intravitreal angiogenic therapy, a subset of neovascular age-related macular degeneration (AMD) patients experience resistance to therapy after repeated injections. Switching drugs could offer benefit to this group of patients.PurposeTo determine visual and anatomical outcomes in a cohort of neovascular AMD patients resistant to repeated injections of bevacizumab/ranibizumab after switching to aflibercept therapy.MethodsThis was a retrospective chart review of patients who had a diagnosis of neovascular AMD and persistent intraretinal (IRF) and/or subretinal fluid (SRF) on optical coherence tomography (OCT) for at least 3 months despite monthly bevacizumab and/or ranibizumab injections prior to transition to aflibercept. We reviewed patients’ records and OCT images obtained at baseline, 1, 3, 6 and 12 months after transition to aflibercept. Data collected included demographics, best-corrected visual acuity (BCVA), number of injections received and the occurrence of any adverse events. Studied OCT parameters included central macular thickness (CMT) values and the presence or absence of SRF, IRF and/or pigment epithelial detachment (PED) at each visit.ResultsWe included 53 eyes of 48 patients. Mean change in BCVA from baseline was 0.05 ± 0.13 (P = 0.01) at M1, 0.04 ± 0.16 (P = 0.08) at M3, 0.01 ± 0.22 (P = 0.9) at M6, and 0.02 ± 0.28 (P = 1) at M12, while the mean change in CMT from baseline was 64 ± 75 μm (P < 0.0001) at M1, 42 ± 85 μm (P = 0.002) at M3, 47 ± 69 μm (P < 0.0001) at M6, and 46 ± 99 μm (P = 0.001) at M12. The percentage of eyes with SRF decreased from 77.4% at baseline to 39.6% at M1, then increased to 47.2% at M3, then decreased to 43.4% at M6, and to 41.5% at M12 (All p < 0.001, compared to baseline). Compared to baseline, there was a statistically significant decrease in the percentage of eyes having IRF from 47.2 to 20.8% at M1 (p < 0.001), 30.2% at M3, 24.5% at M6 and 26.4% at M12 (p < 0.01, each). The number of bevacizumab and/or ranibizumab injections (7.36 ± 1.85) was significantly higher than that of aflibercept (6.47 ± 2.45, p = 0.001). A significant direct relationship between CMT reduction and BCVA improvement was demonstrated at M1 (p = 0.01, r = 0.36), M3 (p = 0.03, r = 0.30) and M12 (p = 0.03, r = 0.30). Eyes with IRF had significantly poorer BCVA than eyes without IRF at baseline (p = 0.02) and M3 (p = 0.04).ConclusionSwitching to intravitreal aflibercept therapy in a cohort of neovascular AMD patients resistant to chronic bevacizumab and/or ranibizumab injections can lead to significant visual improvement in the short term and sustained reduction of central macular thickness over 1 year of followup.

Optical Coherence Tomography Angiography Findings After Intravitreal Ranibizumab in Patients With Coats Disease.

The aim of this retrospective study was to describe the vascular features in eyes with Coats disease, using optical coherence tomography angiography (OCTA), at baseline and after 3 monthly intravitreal injections of ranibizumab. Fifteen eyes of 15 consecutive patients affected by Coats' disease were recruited in this study. All patients underwent the best-corrected visual acuity (BCVA) evaluation, fundus examination, fluorescein angiography (FA), indocyanine green angiography (ICGA), multicolor imaging, structural Spectral Domain (SD)-OCT and OCTA at baseline and 1 month after the third monthly ranibizumab injection (loading phase). Fifteen patients completed the study, of whom nine were males and six females. Mean age was 20.4 ± 2 years. BCVA was 0.46 ± 0.11 logMar and 0.47 ± 0.12 logMar at baseline and after treatment, respectively (p = 0.164). SD-OCT revealed no significant decrease in central macular thickness (486.33 μm ± 93.37 at baseline vs. 483.4 μm ± 80.97 after treatment; p = 0.915). The subretinal exudates persisted in macular region after intravitreal injections. OCTA showed a general vascular rarefaction in superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillary (CC) that did not change after loading phase. This study showed no functional and vascular improvement following 3 monthly ranibizumab injections. OCTA, non-invasive technique, could be useful during follow up of these patients and provide a better understand of pathogenesis of this disorder.

Significance of monitoring vascular endothelial growth factor, monocyte chemoattractant protein-1 and Interleukin-8 in diabetic macular edema towards early identification of nonresponders to ranibizumab therapy.

Purpose:Identification of nonresponders prior to anti-vascular endothelial growth factor (anti-VEGF) therapy would help in the judicious clinical management of diabetic macular edema (DME) patients. Thus, a systematic study was initiated to identify nonresponding DME patient population undergoing ranibizumab treatment to figure out additional inflammatory components that may contribute to their nonresponsiveness to anti-VEGF therapy.Methods:A total of 40 patients recruited to this investigator-initiated trial received intravitreal ranibizumab monthly for 3 months. The fourth- and fifth-month injections were according to PRN protocol and the sixth-month injection was mandatory. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and VEGF in aqueous humor were measured for all the patients. Patients were grouped into responders/nonresponders on the formulated criteria and the levels of key pro-inflammatory cytokines were also measured between the two groups at baseline, 2 month and 5 months using cytometric bead array (CBA).Results:Eleven patients were categorized (29.72%) as responders and 10 patients (27.02%) as nonresponders. Nonresponders showed poorer BCVA (P = 0.024, 0.045, and 0.048 for 4, 5, and 6 months) and higher CMT (P = 0.021, 0.0008 and <0.0001 for baseline, 1, 2, 3, 4, 5, and 6 months) compared to responders. The cytokines IL-8, MCP-1 were significantly up regulated (P = 0.0048 and 0.029 for MCP-1 and IL-8) in nonresponders.Conclusion:Elevated MCP-1 and IL-8 levels found in the nonresponders could be used as a prognostic marker to identify these groups of patients and can help in developing alternative treatment options along with anti-VEGF therapy.