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:

• Efficacy and Safety of Intravitreal Aflibercept Using a T&E Regimen for nAMD: The Aries Study
• Impact of Residual Subretinal Fluid Volumes on Outcomes in a SRF-tolerant T&E Regimen
• Recurrent nAMD After Discontinuation of VEGF Inhibitors Managed in a T&E Regimen
• nAMD Treatment Patterns and Outcomes Over a Decade
• Real-world Outcomes Following Intravitreal Brolucizumab for nAMD: SHIFT Study
• Hypertension and Wet AMD
• Choriocapillaris Flow Deficit & Development of Neovascularization or Atrophy in AMD
• Topical Ketorolac as an Adjunctive Treatment with Intravitreal Bevacizumab in DME Management
• Relationship Between Retinal Vascular Bed Area on WVF FA and DR Severity
• Higher Serum Uric Acid Levels and Risk of Vision-threatening DR
• Computer-aided Detection & Abnormality Score for Outer Retinal Layer on OCT
• Noteworthy

Efficacy and Safety of Intravitreal Aflibercept Using a T&E Regimen for nAMD: The Aries Study

Treating neovascular age-related macular degeneration with intravitreal aflibercept using a treat-and-extend regimen can reduce treatment burden. ARIES investigators assessed whether AFL early-start T&E was noninferior  to late-start T&E.

The randomized, open-label, Phase IIIb/IV study included treatment-naïve patients ages ≥50 years with best-corrected visual acuity of 73 to 25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD.

Patients received 2 mg IVT-AFL at week 0, W4, W8 and W16. At W16, patients were randomized 1:1 to early-start (two-week interval adjustments) or late-start T&E (eight-week intervals until W48, then two-week interval adjustments). The primary endpoint was BCVA change from randomization to W104.

A total of 271 patients were randomized. Mean BCVA at baseline was 60.2 ±12.1 letters (early-start T&E) and 61.3 ±10.8 letters (late-start T&E). Here were some of the findings:
• Mean BCVA change (W16 to 104) was:
   o -2.1 ±11.4 vs. -0.4 ±8.4 letters (early vs. late-start T&E; least-squares mean difference: -2; CI, -4.75 to 0.71; p=0.0162 for NI);
   o +4.3 ±13.4 vs. +7.9 ±11.9 letters (W0 to 104).
• Mean number of injections was 12 ±2.3 vs. 13 ±1.8.
• From baseline to W104, 93.4 percent and 96.2 percent maintained BCVA; mean central retinal thickness change was -161.6 ±135.6 µm and -158.6 ±125.1 µm.
• Last injection interval (W104) was ≥12W for 47.2 percent and 51.9 percent of patients.

Investigators determined that outcomes were similar between nAMD patients treated with an IVT-AFL early- or late-start T&E regimen following initial dosing, with one injection difference over two years.

Impact of Residual Subretinal Fluid Volumes on Outcomes in a SRF-tolerant T&E Regimen  

Researchers looked at associations between residual subretinal fluid (rSRF) volumes and treatment outcomes in an SRF-tolerant treat-and-extend regimen in neovascular age-related macular degeneration.

Patients enrolled in the prospective, multicenter FLUID study randomized in an SRF-tolerant T&E regimen were examined by SD-OCT and tested for best-corrected visual acuity. SRF and intraretinal fluid volumes were quantified using artificial intelligence tools. A total of 375 visits of 98 patients were divided into subgroups: extended intervals despite rSRF and extended intervals without fluid. Associations between BCVA change, SRF volume, subgroups and treatment intervals were estimated using linear mixed models.

Here were some of the findings:
• In extended intervals despite rSRF, increased SRF was associated with reduced BCVA at the next visit in the central 1 mm (-0.138 letters/nl; p=0.014) and 6 mm (-0.024 letters/nl; p=0.049).
• A negative association between increased interval and BCVA change was found for rSRF in 1 and 6 mm (-0.250 and -0.233 letter/week interval, respectively, both p<0.001).
• Extended intervals despite rSRF had significantly higher SRF-volumes in the central 6 mm at the following visit (p=0.002).

Researchers reported that AI-based analysis of extended visits despite rSRF demonstrated increasing SRF-volumes associated with BCVA loss at the consecutive visit. They wrote that this negative association increases understanding about the role of rSRF volumes on treatment outcomes in nAMD.

SOURCE: Grechenig C, Reiter GS, Riedl S, et al. Impact of residual subretinal fluid volumes on treatment outcomes in a SRF-tolerant treat & extend regimen. Retina 2021; Apr 1. [Epub ahead of print.]

Recurrent nAMD After Discontinuation of VEGF Inhibitors Managed in a T&E Regimen

Investigators assessed the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration previously followed in a treat-and-extend regimen in which treatment had been stopped due to disease stability, as part of a prospective cohort study.

A total of 105 nAMD patients previously followed in a treat-and-extend regimen with aflibercept injections were included. All patients with a dry macula on three consecutive visits 12 weeks apart were eligible to participate. Patients were examined at baseline, and then monitored for disease recurrence four, six, eight, 10 and 12 months after the last injection.

Main outcome measures included the proportion of patients with recurrent disease within 12 months after the last injection, and BCVA change at the time of recurrence and after resumed therapy.

Here were some of the findings:
• Evidence of recurrent nAMD was seen in 54/102 patients (52.9 percent) after 12 months of follow-up.
• The mean time to recurrence after the last injection was 6.7 ±2.2 months. The best-corrected visual acuity decreased from 71.7 ±10 ETDRS letters at baseline to 68.1 ±11.1 letters at the recurrence (p=0.12).
• After treatment was resumed BCVA increased to 71.4 ±10 letters (p=NS compared to baseline).
• Patients with a pigment epithelial detachment at baseline had a 74 percent (14/19) recurrence rate compared to 48 percent (40/83) in subjects without a PED (p<0.05).
• Only 22/54 (40.7 percent) of the patients with recurrent disease had symptoms of visual loss or metamorphopsia.

Investigators reported that recurrent nAMD was common in previously stable patients when anti-VEGF injections were suspended. They wrote that it was difficult to predict which patients would have a recurrence, as most didn’t have symptoms in the early stages of reactivation. Investigators stressed the importance of long-term follow-up and noted that early detection of recurrent disease can improve the chances of maintained visual function.

nAMD Treatment Patterns and Outcomes Over a Decade

Management of neovascular age-related macular degeneration has evolved over the last decade with several treatment regimens and different medications. This study described the treatment patterns and visual outcomes over 10 years in a large cohort of patients.

A retrospective analysis of electronic health records from 27 National Health Service secondary care health-care providers in the UK was undertaken. Participants included treatment-naïve patients receiving at least three intravitreal anti-vascular endothelial growth factor injections for nAMD in their first six months of follow-up. Patients with missing data for age or gender, and those under the age of 55 were excluded.

Eyes with at least three years of follow-up were grouped by years of treatment initiation, and three-year outcomes were compared between the groups. Data were generated during routine clinical care between September 2008 and December 2018. Main outcome measures included visual acuity, number of injections and number of visits.

A total of 15,810 eyes of 13,705 patients receiving 194,904 injections were included. Here were some of the findings:
• Visual acuity improved from baseline during the first year, but dropped thereafter, resulting in loss of visual gains. This trend remained consistent throughout the study decade. Although an increasing proportion of eyes remained in the driving standard, this was primarily due to better presenting visual acuities over the decade.
• The number of injections dropped substantially between the first and subsequent years—from a mean of 6.25 in year one, to three in year two and 2.5 in year three, without improvement over the decade.
• In a multivariable regression analysis, final VA improved by 0.24 letters for each year since 2008, and younger age and baseline VA were significantly associated with VA at three years.

Investigators wrote that the findings showed that, despite improvement in functional VA over the years, primarily driven by improving baseline VA, patients continued to lose vision after the first year of treatment, with only marginal change over the next decade. They added that the data suggest the results may be related to suboptimal treatment patterns that haven’t improved over the years. They noted that new treatment approaches such as longer-acting therapies may be warranted.

Real-world Outcomes Following Intravitreal Brolucizumab for nAMD: SHIFT Study

Brolucizumab was recently approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration. Investigators reported on early experiences with real-world outcomes of switching to brolucizumab therapy in previously anti-vascular endothelial growth factor-treated patients. Two of the authors received grants from Novartis.

Patients with recalcitrant nAMD were switched to brolucizumab. Functional and structural parameters four weeks after the first brolucizumab injection were evaluated, including best-corrected visual acuity (logMAR), foveal center point (FCP [µm]), central subfield retinal thickness (CSRT [µm]) and macular volume (mm³).

Sixty-three eyes of 57 patients with nAMD (52.6 percent females) with a mean age of 79.5 ±6.7 years were included. Here were some of the findings:
• Mean change of BCVA was -0.02 ±0.13 logMAR (p=0.322).
• Significant reductions were recorded for FCP with a mean change of -66.79 ±72.64 µm, -66.76 ±60.71 µm for CSRT and -0.27 ±0.24 mm³ for macular volume (all p<0.001).
• Intraocular inflammation was observed in seven eyes of seven patients (11 percent), including one case of retinal vasculitis without occlusion.

Investigators wrote that the SHIFT study findings indicated that the switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. They suggested that further long-term analyses would be helpful to assess the efficacy and safety of brolucizumab in a routine clinical setting.

SOURCE: Bulirsch LM, Saßmannshausen M, Nadal J, et al. Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study. Br J Ophthalmol 2021; Apr 12. [Epub ahead of print].

Hypertension and Wet AMD

Researchers aimed to investigate the association between hypertension, wet age-related macular degeneration and the treatment strategy of wet AMD patients affected by hypertension.

Data of wet AMD patients at Zhongshan Ophthalmic Center, Sun Yat-sen University, between January 2002 and June 2019, were extracted from the electronic health-care information system. Wet AMD patients were divided into subgroups by hypertension status, age, sex, the need for vitrectomy surgery and the number of anti-VEGF drug intravitreal injections (1 to 3 vs. >3).

A total of 3,096 wet AMD patients (41.7 percent female, 58.3 percent male) with an age range of 50 to 96 years (68.7 ±9.42 years) were included. Here were some of the findings:
• Wet AMD was significantly associated with hypertension (p<0.001).
• After adjustment for sex and age, a Cox regression model showed a significant association between hypertension in wet AMD patients and the number of injections (RR=1.31, CI, 1.13 to 1.50; p<0.001).
• No significant association was found between hypertension and the need for vitrectomy (p=0.82).

Researchers wrote that wet AMD was associated with hypertension, and wet AMD patients with hypertension were more likely to receive intravitreal anti-VEGF injections than those without hypertension. They suggested that these results may prompt prospective research on the prevention of wet AMD and may aid in the management of wet AMD patients.

SOURCE: Wang T, Xia J, Yuan M, et al. Hypertension affects the treatment of wet age-related macular degeneration. Acta Ophthalmol 2021; Mar 31. [Epub ahead of print.]

Choriocapillaris Flow Deficit & Development of Neovascularization or Atrophy in AMD

Investigators evaluated the relationship between choriocapillaris flow deficits and structural optical coherence tomography biomarkers, and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) or macular neovascularization (MNV).

Consecutive patients with iAMD were sequentially reviewed to define three equal-sized groups: progressed to MNV; progressed to cRORA; or remained stable over 12 months of follow-up. Odds ratios for progression to cRORA and MNV were estimated by logistic regression for intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDDs), high central drusen volume, fellow eye with late AMD, and peripheral and central choriocapillaris flow deficit.

Thirty iAMD eyes from 30 patients were enrolled into each group. Here are some of the findings:
• The choriocapillaris flow deficit was greater in the peripheral sectors of the macula of eyes which progressed to cRORA compared to the other two groups (p<0.0001).
• The central choriocapillaris flow deficit was also significantly impaired in eyes that progressed to cRORA or MNV compared to eyes that didn’t progress (p=0.001 and p=0.02, respectively).
• Choriocapillaris flow deficits in the peripheral macula were significantly and independently associated with the development of cRORA, while choriocapillaris flow deficits in the center were significantly and independently associated with the development of MNV.

Investigators wrote that while the choriocapillaris was diffusely impaired throughout the macula in intermediate AMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy, it was relatively spared in the more peripheral macula among eyes that progressed to MNV. They suggested that these differential findings may have implications for the pathophysiology of the different late-stage manifestations of AMD.

SOURCE: Corvi F, Corradetti G, Tiosano L, et al. Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021; Apr 26. [Epub ahead of print].

Topical Ketorolac as an Adjunctive Treatment with Intravitreal Bevacizumab in DME Management

Researchers evaluated the additional effect of ketorolac eye drops on therapeutic effects of intravitreal bevacizumab in patients with diabetic macular edema.

In a randomized clinical trial, 50 patients with center-involved DME (macular thickness ≥300 µm accompanied by decreased VA (24 <BCVA ≤70 ETDRS letters) were enrolled consecutively and randomized 1:1 to receive either bevacizumab plus topical ketorolac (25 patients) or bevacizumab plus artificial tears (25 patients). Patients with proliferative diabetic retinopathy, history of intraocular surgery, intravitreal injection less than three months prior, macular photocoagulation less than six months prior and any other concomitant ocular pathologies were excluded from the study.

All patients received three consecutive monthly injections of intravitreal bevacizumab (IVB). After that, patients were examined every six weeks, and reinjection was administered based on the “as needed” protocol if macular thickness was 300 µm or more, and VA was 70 ETDRS letters or less. Patients also received either topical ketorolac or artificial tears three times a day over the study period (six months). Changes in central subfield thickness (CST), best-corrected visual acuity (BCVA, ETDRS letters) and number of IVB injections were compared between the study groups.

Fifty eyes of 50 patients were included (25 eyes in each group). Here were some of the findings:

• The mean CST was significantly decreased in both study groups at the 14th week (-87 ±98 µm; p=0.012 in the bevacizumab plus ketorolac group and -100 ±147 µm; p=0.006 in the bevacizumab plus artificial tears group). The changes of mean CST remained significant only in the bevacizumab plus ketorolac group up to the 26th week (-147 ±124 µm; p<0.001, and -51 ±145 µm; p=0.245, respectively).
• Comparing two groups, reduction of mean CST from baseline was significantly greater in bevacizumab plus ketorolac group compared with the control group at 26th week. (difference=-97 µm, CI,-182 to -11, p=0.017).
• In the study group, mean BCVA significantly increased at both the 20th (6.2 ±10.1, p=0.04) and 26th week (8.2 ±10.9, p=0.03).
• Visual acuity didn’t significantly improve at any time point in the bevacizumab plus artificial tears group. Though insignificant, the 26-week mean change of visual acuity from baseline was greater in the bevacizumab plus ketorolac group (difference=6.5 ETDRS letters; CI, -14.4 to 1.4)
• The two groups were comparable regarding the number of IVB injections (p=0.99).

Researchers wrote that topical ketorolac 0.5% three times a day could enhance and sustain the efficacy of intravitreal bevacizumab in the treatment of DME.

Relationship Between Retinal Vascular Bed Area on WVF FA and DR Severity

Researchers aimed to quantify retinal vascular bed area (RVBA) in square millimeters on stereographically projected ultra-widefield (UWF) fluorescein angiography in eyes with diabetic retinopathy.

The prospective, observational study using baseline Optos 200Tx UWF FA images of 80 eyes with DR from the DAVE and RECOVERY studies were stereographically projected at the Doheny Image Reading Center in Los Angeles, to adjust for peripheral distortion. The early-phase FA frame was used to extract the retinal vasculature as a mask for calculating RVBA. The pixels of the retinal vasculature were automatically computed in square millimeters using manufacturer-provided software.

Eighteen of 80 diabetic eyes were excluded because image quality and contrast were insufficient for automatic extraction of the retinal vasculature from the background fluorescence. The remaining 62 eyes were included in the final analysis. Here are some of the findings:
• In comparison with age-matched and sex-matched normal controls:
   o DR eyes had a higher global RVBA for the entire retina (p<0.001);
   o RVBA correlated with DR severity (p<0.001), with a higher RVBA in eyes with proliferative DR (66.1 ±16.2 mm²) than in those with nonproliferative DR (56.2 ±16.6 mm²) or in normal controls (37.2 ±9.9 mm²). This tendency was also present in the posterior retina and mid-periphery but absent in the far-periphery.
   o RVBA didn’t correlate with retinal ischemia (p>0.05).

Researchers found that DR eyes had a larger global retinal vascular bed area for the entire retina than normal controls, and that RVBA appeared to indicate DR severity. However, they noted, the biomarker wasn’t observed to be a good indicator of retinal ischemia.