Evidence-Based Use of Bevacizumab in the Management of Neovascular Age-Related Macular Degeneration.

Indicated for colorectal cancer for decades, bevacizumab has been widely used off label to treat retinal diseases, and the benefits of its use, specifically in neovascular age-related macular degeneration, have been demonstrated in multiple clinical trials. The intravitreal delivery of bevacizumab requires it to be aseptically repackaged into individual syringes by compounding pharmacies for use in the eye. Although the repackaging process is permitted by the US Food and Drug Administration, the resultant product does not meet the specific standards of products approved for use as ophthalmic injectables nor is the parenteral innovator solution compliant with ophthalmic standards. Studies have also demonstrated variability in the quality and quantity of repackaged bevacizumab. This narrative review summarizes the evidence and discusses the role of off-label bevacizumab in the treatment and management of retinal diseases, its mechanism of action, current challenges and provides a critical appraisal of current evidence, clinical implications, and future directions. [Ophthalmic Surg Lasers Imaging Retina 2024;55:155-162.].

SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance.

PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.

Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy.

PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study - 6 month results.

BACKGROUND/OBJECTIVE: Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD). SUBJECTS/METHODS: Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid. RESULTS: After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 µM (p < 0.001), a - 25.3 µM (p < 0.001) and a - 84.5 µM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 µM (p < 0.001), a - 38.1 µM (p < 0.001) and a - 80.1 µM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved. CONCLUSIONS: Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration.

Cell-based therapies face challenges, including poor cell survival, immune rejection, and integration into pathologic tissue. We conducted an open-label phase 1/2a clinical trial to assess the safety and preliminary efficacy of a subretinal implant consisting of a polarized monolayer of allogeneic human embryonic stem cell-derived retinal pigmented epithelium (RPE) cells in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration. Postmortem histology from one subject with very advanced disease shows the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific human leukocyte antigen (HLA) class I molecules. Markers of RPE cell polarity and phagocytosis suggest donor RPE function. Further histologic examination demonstrated CD34+ structures beneath the implant and CD4+, CD68+, and FoxP3+ cells in the tissue. Despite significant donor-host HLA mismatch, no clinical signs of retinitis, vitreitis, vasculitis, choroiditis, or serologic immune response were detected in the deceased subject or any other subject in the study. Subretinally implanted, HLA-mismatched donor RPE cells survive, express functional markers, and do not elicit clinically detectable intraocular inflammation or serologic immune responses even without long-term immunosuppression.

Retinal non-perfusion in diabetic retinopathy.

Diabetic retinopathy is a major cause of vision loss worldwide and areas of retinal non-perfusion (RNP) are a key pathologic feature of the vascular component of diabetic retinopathy. While there is a need for a more complete understanding of the natural history of RNP development and progression, overall, increasing RNP has been closely linked with worsening DR severity. Both traditional and novel approaches to quantitative image assessment are being explored to advance our understanding of the vascular, physiologic and functional changes associated with progressive RNP. Retinal ischemia secondary to RNP leads to tissue hypoxia and changes in the expression of a host of signalling molecules. Current anti-vascular endothelial growth factor and steroid pharmaceutical agents appear to be unable to reperuse areas of RNP, but may be able to slow the progressive longitudinal accumulation of RNP with regular retreatments. There remains a tremendous unmet need for pharmacotherapies that can slow RNP progression and ultimately reperfuse areas of the non-perfused retina. Towards this end, novel targets including the semaphorin family are being investigated.

One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration.

Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational Relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

Update on Anti-Vascular Endothelial Growth Factor Safety for Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Nowadays, ROP constitutes a leading cause of childhood blindness worldwide and for decades the standard of care has involved peripheral retinal ablation. However, this type of treatment requires the use of specialized equipment by well-trained physicians, has been associated with poor structural and visual outcomes in some preterm infants, and despite its adequate application, some cases of ROP may continue to progress. Therefore, the need for simpler and more efficient strategies made anti-vascular endothelial growth factor (anti-VEGF) medications an appealing option for treatment. Recently, the use of anti-VEGF agents for ROP has increased worldwide; nevertheless, this practice remains off-label, and there is a lack of information regarding its safety profile and the possibility of unfavorable long-term outcomes causes the utmost concern. This review updates the recent evidence regarding the systemic and ocular safety of anti-VEGF treatment for ROP.

Surgical Method for Implantation of a Biosynthetic Retinal Pigment Epithelium Monolayer for Geographic Atrophy: Experience from a Phase 1/2a Study.

PURPOSE: To report the intraoperative methods and anatomic results for subretinal implantation of an investigational human embryonic stem cell-derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate (California Project to Cure Blindness Retinal Pigment Epithelium 1 [CPCB-RPE1]) in geographic atrophy (GA). DESIGN: Single-arm, open label, prospective, nonrandomized, Phase 1/2a study. PARTICIPANTS: Advanced non-neovascular age-related macular degeneration (NNAMD). METHODS: The worse-seeing eye (≤20/200) of each subject underwent subretinal implantation of a single 3.5×6.25 mm CPCB-RPE1 implant with a preplanned primary end point of safety and efficacy at 365 days. Commercially available 23-gauge vitrectomy equipment, custom surgical forceps, and operating microscope with or without intraoperative OCT (iOCT) were used. Exact Wilcoxon rank-sum tests and Spearman rank correlation coefficients were used to assess the association of the percentage of the GA area covered by the implant with patient and surgery characteristics. The partial Spearman correlation coefficient was calculated for the correlation between duration of surgery and baseline GA size after adjustment for surgeon experience. MAIN OUTCOME MEASURES: Intraoperative exploratory measures are reported, including area of GA covered by implant, subretinal position of implant, duration of surgery, and incidence of adverse events. Operative recordings and reports were used to determine exploratory outcome measures. RESULTS: Sixteen subjects were enrolled with a median age of 78 years (range, 69-85 years). Median duration of the surgery for all subjects was 160 minutes (range, 121-466 minutes). Intraoperative OCT was used to guide subretinal placement in 9 cases. Intraoperative OCT was potentially useful in identifying pathology not evident with standard intraoperative visualization. Median GA area at baseline was 13.8 mm2 (range, 6.0-46.4 mm2), and median GA area left uncovered by the implant was 1.7 mm2 (range, 0-20.4 mm2). On average, 86.9% of the baseline GA area was covered by the implant. In 5 subjects, >90% of the GA area was covered. Baseline GA size was inversely correlated with percentage of GA area covered by the implant (rs=-0.72; P = 0.002). No unanticipated serious adverse events related to the implant or surgery were reported. CONCLUSIONS: Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. Intraoperative OCT is not necessary but potentially useful in identifying subretinal pathology and confirming implant location.

Incidence of New Choroidal Neovascularization in Fellow Eyes of Patients With Age-Related Macular Degeneration Treated With Intravitreal Aflibercept or Ranibizumab.

IMPORTANCE: Incidence of conversion to neovascular age-related macular degeneration (nAMD) in untreated fellow eyes of patients who are treated for nAMD in 1 eye with anti-vascular endothelial growth factor agents provides important prognostic information to clinically manage patients. OBJECTIVE: To investigate the association of treatment assignment (intravitreal aflibercept vs ranibizumab) and baseline characteristics with fellow eye conversion to nAMD in the VEGF (Vascular Endothelial Growth Factor) Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the VIEW 1 and VIEW 2 studies (randomized, double-masked, active-controlled, multicenter, 96-week, phase 3 trials comparing the efficacy and safety of intravitreal aflibercept in 2457 patients with treatment-naive eyes with nAMD) analyzed a subgroup of participants treated for nAMD in 1 eye who had untreated fellow eyes without neovascularization at baseline. All participants in the VIEW studies were included in 1 of 4 groups: ranibizumab, 0.5 mg, every 4 weeks; aflibercept, 2 mg, every 4 weeks; aflibercept, 0.5 mg, every 4 weeks; or aflibercept, 2 mg, every 8 weeks after 3 injections at 4-week intervals. Data collection in the VIEW studies occurred from July 2007 to August 2011; the data analysis presented in this report took place from April 2016 to November 2018. INTERVENTIONS: Patients received no treatment in the fellow eyes unless after conversion to nAMD, when any treatment approved by heath authorities was given per the investigators' discretion. MAIN OUTCOMES AND MEASURES: Incidence of conversion to nAMD in patients with untreated fellow eyes that had not had clinical signs of neovascularization at baseline. RESULTS: A total of 1561 participants were included in this analysis. At 96 weeks, 375 patients (24.0%) experienced cases of conversion to neovascular disease in the fellow eye, including 107 of the 399 individuals who received ranibizumab, 0.5 mg, every 4 weeks; 93 of the 387 individuals who received aflibercept, 2 mg, every 4 weeks; 84 of the 387 individuals who received aflibercept, 0.5 mg, every 4 weeks; and 91 of the 388 individuals who received aflibercept, 2 mg, every 8 weeks after 3 doses at 4-week intervals. The rates were 18.1, 16.2, 14.7, and 16.0 per 100 patient-years at risk at week 96, respectively. On multivariate analysis, fellow eye conversion was associated with increasing patient age (per 10 years) at baseline (hazard ratio [HR], 1.20 [95% CI, 1.05-1.36]), female sex (HR, 1.32 [95% CI, 1.06-1.63]), intraretinal fluid in the study eye at baseline (HR, 1.28 [95% CI, 1.02-1.61]), and increasing choroidal neovascularization lesion size (per 10 mm2) in the study eye at baseline (HR, 1.29 [95% CI, 1.06-1.57]). Rates of fellow eye conversion were similar with either of the treatments. CONCLUSIONS AND RELEVANCE: In this secondary analysis of randomized clinical trial data, patients with active nAMD in 1 eye appeared to have a high risk for fellow eye conversion. Such patients should be monitored closely.

Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

LARGE SILICONE DROPLETS AFTER INTRAVITREAL BEVACIZUMAB (AVASTIN).

PURPOSE: Despite its off-label status, intravitreal bevacizumab is the most commonly used intraocular anti-vascular endothelial growth factor agent. Regulation of compounding pharmacies has recently increased to make compounded pharmaceuticals safer. Despite these changes, a marked increase in symptomatic, large silicone oil droplets following intravitreal bevacizumab injections was noticed. METHODS: Retrospective chart review was performed. Within a single private practice, patients who were noted to have large or symptomatic silicone oil bubbles after an intravitreal injection were reviewed. RESULTS: A recent, dramatic increase in the incidence of large or symptomatic silicone oil droplets was noted, with 23 cases noted in the past 5 months, compared with 1 in the previous decade. Patients frequently noted a circular floater consisting of a dark ring surrounding a bright central area immediately following an injection of intravitreal bevacizumab. All bevacizumab injections were from single-piece insulin syringes. B-scan ultrasonography produced a very characteristic reverberation pattern. No inflammation or visual acuity loss was noted because of the droplets; however, some patients were annoyed enough to consider vitrectomy. CONCLUSION: Patients should be carefully evaluated for this possibility, and the characteristic symptom of a round floater consisting of a dark ring surrounding a bright center, and the prominent reverberation pattern on B-scan ultrasonography may help increase detection. Changes in consent forms and discussion of this possibility are indicated while investigation into the cause of this increased incidence continues, especially if one is administering bevacizumab via the one-piece insulin syringes commonly used by compound pharmacies.

A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.

Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD.

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

TREATMENT OF VITREOMACULAR TRACTION WITH INTRAVITREAL PERFLUOROPROPANE (C3F8) INJECTION.

PURPOSE: To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction. METHODS: Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8). RESULTS: Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1-62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block. CONCLUSION: Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy.

The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser.

Comparison of Aflibercept, Bevacizumab, and Ranibizumab for Treatment of Diabetic Macular Edema: Extrapolation of Data to Clinical Practice.

IMPORTANCE: The Diabetic Retinopathy Clinical Research Network (DRCR Network), sponsored by the National Eye Institute, reported the results of a comparative effectiveness randomized clinical trial (RCT) evaluating the 3 anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept (2.0 mg), bevacizumab (1.25 mg), and ranibizumab (0.3 mg) for treatment of diabetic macular edema (DME) involving the center of the retina and associated with visual acuity loss. The many important findings of the RCT prompted the American Society of Retina Specialists to convene a group of experts to provide their perspective regarding clinically relevant findings of the study. OBJECTIVES: To describe specific outcomes of the RCT judged worthy of highlighting, to discuss how these and other clinically relevant results should be considered by specialists treating DME, and to identify unanswered questions that merit consideration before treatment. EVIDENCE REVIEW: The DRCR Network-authored publication on primary outcomes of the comparative effectiveness RCT at 89 sites in the United States. The study period of the RCT was August 22, 2012, to August 28, 2013. FINDINGS: On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and with visual acuity impairment, including mean (SD) improvements by +13.3 (11.1) letters with aflibercept vs +9.7 (10.1) letters with bevacizumab (P < .001) and +11.2 (9.4) letters with ranibizumab (P = .03). Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept (+18.9 [11.5]) over bevacizumab (+11.8 [12.0]) or ranibizumab (14.2 [10.6]) 1 year later (P < .001 for interaction with visual acuity as a continuous variable, and P = .002 for interaction with visual acuity as a categorical variable). It is unknown whether different visual acuity outcomes associated with the use of the 3 anti-VEGF agents would be noted with other treatment regimens or with adequately repackaged bevacizumab, as well as in patients with criteria that excluded them from the RCT, such as persistent DME despite recent anti-VEGF treatment. CONCLUSIONS AND RELEVANCE: On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and visual acuity impairment. Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept over bevacizumab or ranibizumab 1 year later. Care needs to be taken when attempting to extrapolate outcomes of this RCT to differing treatment regimens. With access to adequately repackaged bevacizumab, many specialists might initiate therapy with bevacizumab when visual acuity is good (ie, 20/32 to 20/40 as measured in the DRCR Network), recognizing that the cost-effectiveness of bevacizumab outweighs that of aflibercept or ranibizumab.