FROM THE EDITORS OF REVIEW OF OPHTHALMOLOGY AND RETINA SPECIALIST:

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Ranibizumab Induces DR Regression in Most Cases at High Risk of PDR Progression

Researchers evaluated diabetic retinopathy outcomes with ranibizumab (Lucentis, Genentech) treatment in individuals with DR and diabetic macular edema at high risk of progression to proliferative disease, as part of a post hoc analysis of the Phase III RIDE and RISE clinical trials of ranibizumab for the treatment of DME.

A total of 746 individuals with baseline fundus photographs were randomized for treatment. Researchers assessed DR outcomes through month 36 by baseline DR severity level. They quantified DR severity using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale. Main outcome measures included two-step or more, or three-step or more, improvements or worsening on the ETDRS DRSS and time to new proliferative event (composite end point). Researchers reported the following findings.
• At baseline, most individuals were distributed evenly among mild or moderate nonproliferative DR (ETDRS DRSS, 35/43; 28.8 percent), moderately severe or severe NPDR (ETDRS DRSS, 47/53; 33.2 percent), and proliferative DR (ETDRS DRSS, 60 to 75; 31.1 percent).
• At month 24, rates of two-step or more improvement with ranibizumab 0.3 mg (78.4 percent), ranibizumab 0.5 mg (81.1 percent) and sham treatment (11.6 percent) were highest among individuals with baseline DR levels 47/53 compared with individuals with baseline DR levels 35/43 (ranibizumab 0.3 mg, [10.3 percent], ranibizumab 0.5 mg [15.8 percent] and sham treatment [1.4 percent]); or 60 to 75 without panretinal photocoagulation (ranibizumab 0.3 mg [31 percent], ranibizumab 0.5 mg [36.4 percent] and sham treatment [6.7 percent]; all ranibizumab vs. sham comparisons, p<0.05).
• In individuals with baseline DR levels 47/53, ranibizumab treatment reduced the probability of individuals experiencing a new proliferative event at month 36 by three times compared with sham treatment (ranibizumab 0.3 mg [12.4 percent] and ranibizumab 0.5 mg [11.9 percent] and sham [35.2 percent]).
• In individuals with baseline DR levels 47/53 who achieved two-step or more DR improvement, improvements were independent of all assessed baseline characteristics (p>0.4).

Researchers concluded that ranibizumab treatments resulted in DR improvements in all three baseline DR severity subsets examined. They added that the greatest benefits in DR improvement occurred in individuals with baseline moderately severe to severe NPDR (DR levels 47/53), and that DR improvements were rapid, clinically meaningful and sustained through month 36.

SOURCE: Wykoff CC, Eichenbaum DA, Roth DB, et al. Ranibizumab induces regression of diabetic retinopathy in most patients at high risk of progression to proliferative diabetic retinopathy. Ophthalmology Retina 2018; Aug. 1. [Epub ahead of print].

Panretinal Photocoagulation vs. Intravitreous Ranibizumab for PDR

Investigators evaluated the efficacy and safety of 0.5-mg intravitreous ranibizumab vs. panretinal photocoagulation over five years for proliferative diabetic retinopathy. They evaluated 394 study eyes in the Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial with PDR, enrolled February through December 2012.

Eyes were randomly assigned to receive intravitreous ranibizumab (n=191) or PRP (n=203). The frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. The main outcome was mean change in visual acuity (intention-to-treat analysis). Secondary outcomes included peripheral visual field loss, development of vision-impairing DME and ocular and systemic safety.

The five-year visit was completed by 184 of 277 participants (66 percent excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years; 135 (44 percent) were women and 160 (52 percent) were white.

For the ranibizumab and PRP groups, respectively:
• the mean (SD) number of injections over five years was 19.2 (10.9) and 5.4 (7.9);
• the mean (SD) change in VA letter score was 3.1 (14.3) and three (10.5) letters (adjusted difference, 0.6; CI, -2.3 to 3.5; p=0.68);
• the mean VA was 20/25 (approximate Snellen equivalent) in both groups at five years; and
• the mean (SD) change in cumulative VF total point score was -330 (645) (n=41) vs. -527 (635) dB (n=38) groups (adjusted difference, 208 dB; CI, 9 to 408);
• vision-impairing DME developed in 27 vs. 53 eyes (cumulative probabilities: 22 percent vs. 38 percent; HR, 0.4; CI, 0.3 to 0.7); and
• there were no statistically significant differences between groups in terms of major systemic adverse event rates.

Investigators wrote that, although loss to follow-up was relatively high, VA in most study eyes that completed follow-up was very good at five years and similar in both groups. They added that severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing DME and less VF loss. Lastly, they wrote that the findings supported anti-vascular endothelial growth factor therapy or PRP as viable treatments for PDR. Investigators suggested that clinicians should consider patient-specific factors—including anticipated visit compliance, cost and frequency of visits—when choosing treatment for individuals with PDR.

SOURCE: Gross JG, Glassman AR, Liu D, et al. Five-year outcomes of panretinal photocoagulation vs. intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA Ophthalmol 2018; Jul 24. [Epub ahead of print].

Anti-VEGF Therapy in DME: Real-world Outcomes

Researchers assessed real-world visual acuity outcomes of anti-vascular endothelial growth factor therapy for diabetic macular edema. They performed a retrospective analysis on the Vestrum Health Retina Database of aggregated, longitudinal electronic medical records from a geographically and demographically diverse sample of cases of U.S. retina specialists.

Participants included DME eyes that underwent ≥3 monthly anti-VEGF injections within four months of the first injection (between January 2011 and March 2017) with follow-up data prior to March 2018.

The eyes were divided into three groups based on initial intravitreal anti-VEGF agents (aflibercept, bevacizumab or ranibizumab). These eyes were subdivided into three cohorts by length of follow-up (six, 12 or 24 months), with each cohort being mutually exclusive. Researchers assessed VA outcomes and number of treatments on each cohort, and stratified the results by baseline VA. A total of 15,608 DME eyes were included.

In the 12-month cohort, of 1,379 eyes initially treated with aflibercept:
• the mean 12-month improvement was +5.5 letters (CI, +4.5 to +6.6 letters, p<0.001) after 7.5 injections on average, with similar outcomes for bevacizumab (3,109 eyes, +5.5 letters; CI, +4.7 to +6.3 letters, p<0.001, average 7.9 injections) and ranibizumab (1,352 eyes, +4 letters; CI, +2.9 to +5.2 letters, p<0.001, average 7.7 injections).

The mean number of corticosteroid, and macular and panretinal laser treatment sessions were similar in each group. In the 12-month cohort, when stratified by baseline VA (in parentheses):
• in the aflibercept group, the final mean letters gained or lost were: +28 (20/201 or worse); +10.2 (20/71 to 20/200); +2.8 (20/41 to 20/70); and -2.5 (20/40 or better);
• in the bevacizumab group, the final mean letters gained or lost were: +36 (20/201 or worse); +7.8 (20/71 to 20/200); +2.9 (20/41 to 20/70); and -2 (20/40 or better) letters; and
• in the ranibizumab group, the final mean letters gained or lost were: +30.5 (20/201 or worse); +7.9 (20/71 to 20/200); +1.6 (20/41 to 20/70); and -2.7 (20/40 or better).

Researchers concluded real-world VA outcomes following anti-VEGF therapy for DME were meaningfully inferior to those noted in randomized, controlled trials. They added that eyes with better baseline VA gained fewer letters compared with those with worse baseline VA and that the initial choice of anti-VEGF agent didn’t correlate with visual outcomes.

SOURCE: Ciulla TA, Bracha P, Pollack J, et al. Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States. Ophthalmology Retina 2018; July 28. [Epub ahead of print].

Structural Neurodegeneration Correlates with Early Diabetic Retinopathy

Investigators examined differences in structural and functional neurodegenerative measurements between individuals with no and early diabetic retinopathy, as part of a cross-sectional study.

They examined 103 people with type 2 diabetes mellitus. In 7-field fundus photographs acquired with the Topcon TRC-NW6S, a single, certified grader determined the presence of DR according to the Early Treatment Diabetic Retinopathy Study scale. Retinal neurodegeneration was evaluated using Topcon 3D OCT-2000 spectral-domain optical coherence tomography and RETI-scan multifocal electroretinography (mf-ERG) system in rings one to six.

Median age of diabetes was 63.6, and mean duration was 10 years; 46 percent of participants were men. Median HbA1c was 50 mmol/mol (6.7 percent) and ETDRS levels were 10 (41.7 percent, n=43), 20 (35 percent, n=36) and 35 (23.3 percent, n=24). The duration of diabetes increased with higher levels of DR (p=0.04), but individuals with different levels of DR didn’t differ according to age, sex, blood pressure, HbA1c and mf-ERG or OCT parameters. In a multiple logistic regression model, macular ganglion cell layer thickness was associated with presence of DR (OR 1.73 per 5 μm increase, CI 1.06 to 2.85, p=0.03). Conversely, retinal nerve fiber layer thickness at the optic disc was inversely related to DR (OR 0.69 per 5 μm increase, CI 0.51 to 0.95, p=0.02). Investigators found no associations between DR and mf-ERG outcomes.

Investigators determined that structural neurogenic characteristics were associated with DR in individuals with type 2 diabetes. They wrote that, if the findings were confirmed by larger prospective studies, the results might indicate that complex neurovascular interactions were early events in the pathogenesis of DR.

Source: Frydkjaer-Olsen U, Soegaard Hansen R, Peto T, et al. Structural neurodegeneration correlates with early diabetic retinopathy. Int Ophthalmol 2018;38:4:1621-6.

Safety & Efficacy of Anti-VEGF Therapies for Neovascular AMD

Researchers reviewed the evidence on the safety and efficacy of anti-vascular endothelial growth factor therapies to treat neovascular age-related macular degeneration, via a literature search of the PubMed and Cochrane Library databases last reviewed February 2017.

Combined searches, limited to studies published in English, yielded 191 citations, 28 of which were selected because they were clinical trials deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous Panel to review in full. The panel methodologist then assigned a level of evidence rating to each study.

Sixteen of 28 citations provided level I evidence supporting the use of anti-VEGF agents for neovascular AMD, including intravitreal ranibizumab, aflibercept and bevacizumab. Eight studies provided level II evidence, and four provided level III evidence (only level I studies were included in the assessment). Long-term follow-up data on the efficacy of ranibizumab and bevacizumab (≥5 years) was available; however, researchers noted that this data is biased by some incomplete follow-ups.

Researchers determined that their literature review indicated that intravitreal injection of anti-VEGF therapy was safe and effective for nAMD over two years—the period for which data is available. They added that further research would be needed to evaluate the long-term safety and comparative efficacy of these agents.

SOURCE: Bakri SJ, Thorne JE, Ho AC, et al. Safety and efficacy of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration. Ophthalmology 2018; Aug 2. [Epub ahead of print].

OCT, FA & Diagnosis of CNV in AMD

Scientists determined the sensitivity and specificity of different retinal imaging combinations to diagnose choroidal neovascularization in age-related macular degeneration.

Individuals age 50 or older referred for suspicious recent-onset CNV related to AMD were prospectively studied for six months. Data recorded included color fundus photographs, spectral-domain optical coherence tomography and fluorescein angiography images. Five retina specialists randomly interpreted SD-OCT combined with CFP and FA combined with CFP. The reference diagnosis of CNV was based on the agreement of two readers’ interpretation of SD-OCT + FA + CFP combination. A total of 148 (148 eyes) were included. The researchers’ results included:

• For CNV diagnosis, the sensitivity of SD-OCT + CFP and FA + CFP was 90.9 percent.
• Type 2 CNV was diagnosed in 98 to 100 percent of cases with SD-OCT + CFP or FA + CFP.
• Type 1 CNV was diagnosed in 82.9 percent of cases with SD-OCT + CFP and 81.6 percent with FA + CFP.

Scientists wrote that SD-OCT combined with CFP had sensitivity and specificity similar to those of FA combined with CFP when used as a first diagnostic test for CNV in AMD. They added that the results pointed to the increasingly important role of SD-OCT as a first-line test in diagnosing CNV.

SOURCE: Gualino V, Tadayoni R, Cohen SY, et al. Optical coherence tomography, fluorescein angiography, and diagnosis of choroidal neovascularization in age-related macular degeneration. Retina 2018; Jul 24. [Epub ahead of print].

Fractal Dimension & OCTA Features of Central Macula After RRD Repair

Investigators wrote that individuals with macula-off rhegmatogenous retinal detachments might have suboptimal visual recovery despite successful reattachment. They evaluated the retinal microvasculature in subjects undergoing surgery for RRD using optical coherence tomography angiography.

In this case-control study, investigators compared analyses of OCTA findings of 19 eyes of 19 individuals (15 men) who underwent RRD surgery at a tertiary institute with 19 eyes of 19 age- and sex-matched healthy subjects with no known ocular disease. OCTA scans (3 × 3 mm) were obtained at three months postoperatively and analyzed. Researchers analyzed OCTA images of individuals with RRD and control subjects for capillary density index and fractal dimensions.

The mean age for study eyes was 40.21 years and 43.73 years for control eyes. Eight eyes underwent scleral buckling alone, and 11 underwent primary vitrectomy with gas tamponade (C3F8 gas) for macula-off RRD. No eyes had re-detachment during the follow-up at three months. Mean capillary density index was 33.28 ±0.99 percent in the superficial group and 34.06 ±2.22 percent in the deep retinal plexus group, compared with 36.11 ±1.29 percent in the superficial group and 37.52 ±1.24 in the deep retinal plexus group, among controls (p<0.001). The mean fractal dimension was lower in study eyes compared with controls: 1.46 vs. 1.61 in the superficial plexus group (p<0.001) and 1.58 vs. 1.64 in the deep plexus group (p<0.001).

Investigators concluded that OCTA demonstrated significant reduction in mean capillary density index and fractal dimension in individuals after surgery for RRD. As such, they suggested that reduction in vascular perfusion and branching patterns identified using novel analysis techniques on OCTA images might provide an insight into the reasons for suboptimal visual gain after RRD surgery.

SOURCE: Agarwal A, Aggarwal K, Akella Madhuri, et al. Fractal dimension and optical coherence tomography angiography features of the central macula after repair of rhegmatogenous retinal detachments. Retina 2018; Aug. 3. [Epub ahead of print].