THE LATEST PUBLISHED RESEARCH

Welcome to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• Aflibercept for Retinal Nonperfusion in PDR
• Vitrectomy for Diabetic Complications: A Pooled Analysis
• Prevalence & Treatment of DME and Vision-threatening DR Among Medicare Part B Beneficiaries
• OCT Reveals Rod Photoreceptor Degeneration in Early DR
• MNV Lesion Type and Vision Outcomes in AMD: Post Hoc Analysis of HARBOR
• Brolucizumab for Pre-treated Patients with CNV & Signs of Tachyphylaxis to Aflibercept and Bevacizumab
• Fundus Autofluorescence and En Face OCT Measurements of GA
• Laser & Anti-VEGF Treatment for Drusenoid PED in AMD
• Plasma Omega-3 Fatty Acids & Early AMD
• Association of Choroidal Thickness with RRD Repair
  
• Noteworthy

Aflibercept for Retinal Nonperfusion in PDR

Investigators in Regeneron’s RECOVERY study note that retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy. Data suggests that consistent anti-VEGF pharmacotherapy can slow RNP development, the researchers add. RECOVERY evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR.

This prospective randomized clinical trial with treatment crossover in the second year looked at eyes with PDR and RNP.

At baseline, subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2-mg aflibercept. At the beginning of year two, the treatment arms were crossed over so monthly dosed subjects subsequently received quarterly dosing while quarterly dosed subjects subsequently received monthly dosing.

Main outcome measures included change in total RNP area through year two. Secondary outcomes included DR severity scale (DRSS) scores, best-corrected visual acuity, central subfield thickness, additional measures of RNP including ischemic index (ISI) and adverse events incidence. Means and 95 percent confidence intervals were calculated.

Here are some of the findings:
• Among all subjects from baseline to year two, mean RNP increased from 235 mm² to 402 mm² (p<0.0001), and ISI increased from 25.8 to 50.4 percent (p<0.0001).
• Increases in mean RNP (p<0.0001) and ISI (p<0.0001) were also observed from year one to two.
• Mean total RNP increased from 264 mm² at baseline to 386 mm² (p<0.0001) at year two in arm 1 and from 207 mm² at baseline to 421 mm² (p<0.0001) at year two in arm 2 (p=0.023; arm 1 vs. 2).
• Increases in mean RNP for both treatment arms (p<0.0001) were also observed specifically within year two (p=0.32, arms 1 vs. 2).
• Compared with baseline, DRSS scores at the end of year two improved in 82 percent (n=27) of subjects and remained stable in 18 percent (n=6), with no subject experiencing worsening; at two years, DRSS scores had improved by two or more steps in 65 percent (n=11) of subjects in arm 1 and 81 percent (n=13) in arm 2.

Investigators wrote that through year two of RECOVERY, both treatment arms experienced significant increases in retinal nonperfusion. Despite expansion of RNP area in nearly all subjects, 82 percent demonstrated an improvement in DRSS levels from baseline with no subject experiencing worsening in DRSS.

SOURCE: Wykoff CC, Nittala MG, Boone CV, et al; RECOVERY Study Group. Final outcomes from the randomized RECOVERY trial of alfibercept for retinal nonperfusion in proliferative diabetic retinopathy. Ophthalmol Retina 2022; Mar 4. [Epub ahead of print].

Vitrectomy for Diabetic Complications: A Pooled Analysis

Investigators reported updated clinical outcomes in subjects undergoing pars plana vitrectomy using modern techniques and equipment for the treatment of proliferative diabetic retinopathy-related complications.

The pooled analysis included five randomized clinical trials conducted at the same institution, and study and control subjects from the trials.

A total of 943 subjects prospectively underwent small-gauge PPV with anti-vascular endothelial growth factor pretreatment for PDR-related complications and completed six-month follow up.

Here are some of the findings:
• One hundred eighty-four patients (19.5 percent) achieved 20/50 or better acuity, and 652 patients (69.1 percent) achieved 20/200 or better acuity at six months.
• The vision improved or remained stable in 901 patients (95.5 percent), and 11 patients (1.2 percent) developed no light perception at six months.
• Intraoperative complications occurred in 343 cases (36.4 percent) of cases, and 199 cases (21.1 percent) experienced a postoperative complication.
• The most common postoperative complication was vitreous hemorrhage in 124 cases (62.3 percent of all complications).
• Unplanned secondary PPV was necessary in 86 cases (9.1 percent).

Investigators wrote that clinical outcomes in patients undergoing PPV for PDR-related complications compared favorably to those reported prior to small-gauge PPV and anti-VEGF pretreatment.

SOURCE: Rush RB, Rush SW, Reinauer RM, et al. Vitrectomy for diabetic complications: A pooled analysis of randomized controlled trials utilizing modern techniques and equipment. Retina 2022; Mar 8. [Epub ahead of print].

Prevalence & Treatment of DME and Vision-threatening DR Among Medicare Part B Beneficiaries

Researchers wrote that, while diabetes prevalence among U.S. adults has increased in recent decades, few studies document trends in diabetes-related eye disease.

They examined 10-year trends (2009 to 2018) in annual prevalence of Medicare beneficiaries with diabetes with a diagnosis of diabetic macular edema or vision-threatening diabetic retinopathy (VTDR), and looked at trends in treatment.

In this cross-sectional study using Centers for Medicare & Medicaid Services research identifiable files, data for patients 65 years and older were analyzed from claims. Beneficiaries were continuously enrolled in Medicare Part B fee-for-service insurance for the calendar year and had a diagnosis of diabetes on one or more inpatient claims, or two or more outpatient claims during the calendar year or one-year period.

Using diagnosis and procedure codes, annual prevalence was determined for beneficiaries with one or more claims for:

• (1) any DME;
• (2) either DME or VTDR; or
• (3) anti-vascular endothelial growth factor injections, laser photocoagulation or vitrectomy, stratified by any DME, VTDR with DME, or VTDR without DME.

Racial and ethnic disparities in diagnoses and treatment were presented for 2018.

In 2018, 6,960,823 beneficiaries (27.4 percent) had diabetes. Half were ages 65 to 74 years (49.7 percent), half (52.7 percent) were women and 75.7 percent were non-Hispanic White. Here are some of the findings:

• From 2009 to 2018, an increase was found in the annual prevalence of beneficiaries with diabetes who had one or more claims for any DME (1 to 3.3 percent) and DME/VTDR (2.8 to 4.3 percent).
• Annual prevalence of anti-VEGF increased, particularly among patients with any DME (15.7 to 35.2 percent) or VTDR with DME (20.2 to 47.6 percent).
• Annual prevalence of laser photocoagulation decreased among those with:
• DME (45.5 to 12.5 percent);
• VTDR with DME (54 to 20.3 percent); or
• VTDR without DME (22.5 to 5.8 percent).
• Among all three groups, prevalence of vitrectomy in 2018 was less than half that in 2009.
• Prevalence of any DME and DME/VTDR was highest among Hispanic beneficiaries (5 and 7 percent, respectively) and Black beneficiaries (4.5 and 6.2 percent, respectively), and lowest among non-Hispanic White beneficiaries (3 and 3.8 percent, respectively).
• Among those with DME/VTDR, anti-VEGF was most prevalent among non-Hispanic White beneficiaries (30.3 percent).

Researchers reported that, from 2009 to 2018, prevalence of DME or VTDR increased among Medicare Part B FFS beneficiaries in tandem with an increase in anti-VEGF treatment, and decline in laser photocoagulation and vitrectomy.

SOURCE: Lundeen EA, Andes LJ, Rein DB, et al. Trends in prevalence and treatment of diabetic macular edema and vision-threatening diabetic retinopathy among Medicare Part B fee-for-service beneficiaries. JAMA Ophthalmol 2022; Mar 3. [Epub ahead of print].

OCT Reveals Rod Photoreceptor Degeneration in Early DR

This study evaluated the feasibility of optical coherence tomography detection of photoreceptor abnormality and verified whether the photoreceptor abnormality was predominantly in rods in early diabetic retinopathy.

Investigators acquired OCT images from normal eyes, diabetic eyes with no diabetic retinopathy (NoDR) and those with mild NPDR. Investigators determined quantitative features, including thickness measurements quantifying band distances and reflectance intensity features among the external limiting membrane (ELM), inner segment ellipsoid (ISe), interdigitation zone (IZ) and retinal pigment epithelium. Comparative OCT analysis of the central fovea, parafovea and perifovea were implemented to verify the photoreceptor abnormality was predominately in rods in early DR.

Thickness abnormalities between the ISe and IZ showed a decreasing trend among cohorts. Investigators observed reflectance abnormalities of the ELM, IZ and ISe between healthy, NoDR, and mild NPDR eyes. The normalized ISe/RPE intensity ratio revealed a significant decreasing trend in the perifovea, but no detectable difference in the central fovea.

Quantitative OCT analysis consistently revealed outer retina, i.e., photoreceptor, changes in diabetic patients with NoDR and mild NPDR. Investigators wrote that comparative analysis of the central fovea, parafovea and perifovea confirmed that the photoreceptor abnormality was predominantly in rods in early DR.

SOURCE: Le D, Son T, Lim JI, Yao X. Quantitative optical coherence tomography reveals rod photoreceptor degeneration in early diabetic retinopathy. Retina 2022; Mar 11. [Epub ahead of print].

MNV Lesion Type and Vision Outcomes in AMD: Post Hoc Analysis of HARBOR

Researchers characterized the relationships between Consensus on Neovascular Age-Related Macular Degeneration Nomenclature (CONAN) Study Group classifications of macular neovascularization and visual responses to ranibizumab in patients with neovascular age-related macular degeneration.

This post hoc analysis of the Phase III HARBOR trial of ranibizumab in nAMD included analyses of:
• ranibizumab-treated eyes with baseline multimodal imaging data;
• baseline MNV;
• subretinal and/or intraretinal fluid at screening, baseline or week 1; and
• spectral-domain optical coherence tomography images through month 24 (n=700).
Mean best-corrected visual acuity over time and mean BCVA change at months 12 and 24 were compared between eyes with type 1, type 2/mixed type 1 and 2 (type 2/M), and any type 3 MNV at baseline.

Here are some of the findings:
• At baseline, 263 eyes (37.6 percent) had type 1, 287 eyes (41 percent) had type 2/M, and 150 eyes (21.4 percent) had any type 3 lesions.
• Type 1 eyes had the best mean BCVA at baseline (59; CI, 57.7 to 60.3 letters) and month 24 BCVA (67.7; CI, 65.8 to 69.6 letters).
• Type 2/M eyes had the worst mean BCVA (50; CI, 48.6 to 51.4 letters) and month 24 BCVA (60.8; CI, 58.7 to 62.9 letters).
• Mean BCVA gains at month 24 were most pronounced for type 2/M eyes (10.8; CI, 8.9 to 12.7 letters), and similar for type 1 (8.7; CI, 6.9 to 10.5 letters) and any type 3 eyes (8.3; CI, 6.3 to 10.3 letters).

Researchers found that differences in BCVA outcomes between CONAN lesion type subgroups supported the use of an anatomic classification system to characterize MNV and prognosticate visual responses to anti-vascular endothelial growth factor therapy for nAMD.

SOURCE: Freund KB, Staurenghi G, Jung JJ, et al. Macular neovascularization lesion type and vision outcomes in neovascular age-related macular degeneration: Post hoc analysis of HARBOR. Graefes Arch Clin Exp Ophthalmol 2022; Mar 3. [Epub ahead of print].

Brolucizumab for Pre-treated Patients with CNV & Signs of Tachyphylaxis to Aflibercept and Bevacizumab

Researchers wrote that treatment of choroidal neovascularization due to age-related macular degeneration is challenging since an increasing number of patients show reduced morphological response to conventional treatment with intravitreal injections. This study tested the hypothesis that the newly introduced anti-VEGF antibody brolucizumab shows promising results in pre-treated patients, as well as in cases of tachyphylaxis to aflibercept or bevacizumab.

Thirty-six eyes of 34 patients with a history of at least 10 anti-VEGF injections as well as persistent retinal fluid following the past five monthly injections with aflibercept and bevacizumab, prior to first treatment with brolucizumab, were included. Morphological and functional treatment responses were compared before and after switching to brolucizumab.

Here are some of the findings:
• Mean best-corrected visual acuity didn’t significantly change after treatment with brolucizumab.
• Central retinal thickness significantly decreased four weeks after treatment with brolucizumab from 340.36 to 282.22 µm (p<0.001), as well as pigment epithelial detachment from 346.73 to 280.47 µm (p<0.001).
• In 24 eyes (66.67 percent), complete resolution of intra- and subretinal fluid was observed after a single dose of brolucizumab.
• No serious adverse events, such as intraocular inflammation and retinal vasculitis, were reported after a single injection of brolucizumab.

Researchers reported that brolucizumab was effective not only in treatment-naïve patients, as shown in the HAWK and Harrier trials, but also in pre-treated patients. They added that the data also suggested that brolucizumab was effective in patients with signs of tachyphylaxis to other anti-VEGF agents.

SOURCE: Boltz A, Radunsky K, Weingessel B, et al. Brolucizumab for pre-treated patients with choroidal neovascularization and signs of tachyphylaxis to aflibercept and bevacizumab. Graefes Arch Clin Exp Ophthalmol 2022; Mar 29. [Epub ahead of print].

Fundus Autofluorescence and En Face OCT Measurements of GA

Investigators evaluated the correlation between fundus autofluorescence and en face spectral-domain optical coherence tomography measurements of geographic atrophy associated with age-related macular degeneration, as part of a retrospective, cross-sectional study.

A total of 270 eyes from 172 subjects with GA associated with AMD were included. Subjects with atrophic AMD with both FAF (Heidelberg HRA + Spectralis) and dense volume (128 B-scans over 6 x 6 mm) SD-OCT (Cirrus OCT) imaging were included in this retrospective analysis.

The borders of all areas of definite decreased autofluorescence (DDAF) corresponding to GA were manually outlined on FAF images by certified graders at the Doheny Image Reading Center (DIRC) using validated planimetric grading tools. In addition, GA was delineated automatically from en face OCT (at the level of the choroid) using instrument software (Cirrus v.6.2), and segmentation errors were manually corrected prior to computation of the GA area. FAF- and SD-OCT-derived measurements were correlated. Main outcome measures included correlation between SD-OCT and FAF measurements of GA area.

Here are some of the findings:
• The mean GA area measured from FAF images was 8.1 ±5.04 mm², compared with an automated, uncorrected SD-OCT GA area of 6.82 ±3.84 mm².
• Despite the presence of apparent OCT segmentation errors, a significant correlation was found between FAF and uncorrected SD-OCT measurements (r=0.80; p<0.001).
• Following manual correction of SD-OCT GA segmentation errors, the measured GA area increased to 7.29 ±4.18 mm², and the correlation with the FAF-determined GA area significantly improved (r=0.98; p<0.001).

Investigators reported that SD-OCT-derived measurements of GA correlated well with areas of definite decreased autofluorescence obtained from fundus autofluorescence images. As such, they wrote that manual correction of SD-OCT segmentation errors can further improve this correlation.

SOURCE: Velaga SB, Nittala MG, Hariri A, et al. Correlation between fundus autofluorescence and en face optical coherence tomography measurements of geographic atrophy. Ophthalmol Retina 2022; Mar 22. [Epub ahead of print].

Laser & Anti-VEGF Treatment for Drusenoid PED in AMD

Researchers investigated the 24-month primary endpoint outcomes of drusenoid pigment epithelial detachment after laser and intravitreal anti-VEGF treatment following a 12-month interim safety analysis.

Twenty-one patients with treatment-naïve bilateral intermediate AMD with dPED and visual acuity ≤83 letters (Snellen 20/23) were enrolled. The subject eye received low-energy Pascal laser (532 nm) treatment, and the fellow eye was used as the control. Intravitreal injections were administered at three-month intervals from baseline to 12 months. Treatment outcomes, safety and development of advanced AMD lesions were analyzed.

Here are some of the findings:
• Mean drusen area and dPED height were significantly reduced (17.3 ±2.7 percent vs. 112.8 ±3.1 percent, p<0.001 and 11.8 ±4.7 percent vs. 119.1 ±4.6 percent, p<0.001, respectively).
• Mean BCVA improved (5.11 ±1.35 vs. 0.83 ±1.03 letters, p=0.014) in study eyes compared to those in the control eyes.
• Development of parafoveal iRORA (nGA) (67 percent, 12 of 18 eyes) and cRORA (GA) (22 percent, four of 18 eyes) was observed in study eyes.
• Three cases of iRORA and cRORA were observed in control eyes (17 percent, three of 18 eyes; p=0.010 and p=0.791, respectively).

Researchers wrote that laser and anti-VEGF treatment may be a potential treatment option for intermediate AMD with dPED. However, they added, the relatively high rate of secondary iRORA and cRORA development suggested that long-term follow-up is necessary to clarify the safety and efficacy of the treatment.

SOURCE: Kim MS, Ryoo NK, Park KH. Laser and anti-vascular endothelial growth factor treatment for drusenoid pigment epithelial detachment in age-related macular degeneration: 24-month outcomes. Graefes Arch Clin Exp Ophthalmol 2022; Mar 21. [Epub ahead of print].

Plasma Omega-3 Fatty Acids & Early AMD

Researchers examined the association between omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and age-related macular degeneration in the Multi-ethnic Study of Atherosclerosis (MESA) cohort.

MESA was a multicenter, prospective cohort study studying risk factors for cardiovascular disease in four ethnic groups. A total of 6,814 participants of White, African-American, Hispanic/Latino and Chinese descent, ages 45 to 84 years, were recruited. Those found to have cardiovascular disease were excluded.

The study population included all MESA participants with baseline PUFA measurements and retinal photography at exam five (n=3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression (log-link) determined associations between PUFA levels and AMD.

Researchers found a significant association between increasing DHA levels and increasing DHA + EPA levels with reduced risk for early AMD (n=214 participants with early AMD; n=99 [46.3 percent] were non-White). EPA levels alone weren’t significantly associated with AMD.

Researchers found that increasing levels of DHA were associated with reduced risk for early AMD in a multi-ethnic cohort. They wrote that the study represented the first racially diverse study demonstrating an association between omega-3 PUFAs and AMD risk.

SOURCE: Karger AB, Guan W, Nomura SO, et al. Association of plasma ω-3 fatty acids with early age-related macular degeneration in the Multi-Ethnic Study of Atherosclerosis (MESA). Retina 2022; Mar 9. [Epub ahead of print].