Over the past two decades, the Diabetic Retinopathy Clinical Research Network (now known as the DRCR Retina Network) has contributed to multiple and substantial advances in the clinical care of ...diabetic eye disease. Network studies helped establish anti-vascular endothelial growth factor (VEGF) agents as an effective alternative to panretinal photocoagulation for eyes with proliferative diabetic retinopathy (PDR) and as first-line therapy for eyes with visual impairment for diabetic macular edema (DME), defined treatment algorithms for the use of intravitreal medications in these conditions, and provided critical data to understand how to better evaluate the diabetic eye using optical coherence tomography and other imaging modalities. Ongoing DRCR.net studies will address whether anti-VEGF therapy is effective at preventing vision-threatening complications in eyes with severe non-proliferative diabetic retinopathy, if photobiomodulation has a beneficial effect in eyes with DME, and whether initiation of DME treatment with bevacizumab and rescue with aflibercept can provide visual outcomes as good as those achieved with aflibercept alone. Future plans for the Network also include the expansion into non-diabetic eye disease in areas such as age-related macular degeneration.
To report 5-year results from a previously reported trial evaluating intravitreal 0.5 mg ranibizumab with prompt versus deferred (for ≥24 weeks) focal/grid laser treatment for diabetic macular edema ...(DME).
Multicenter, randomized clinical trial.
Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit in the prompt and deferred groups, respectively.
Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and prompt or deferred (≥24 weeks) focal/grid laser treatment.
Best-corrected visual acuity at the 5-year visit.
The mean change in visual acuity letter score from baseline to the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference, -2.6 letters; 95% confidence interval, -5.5 to +0.4 letters; P = 0.09). At the 5-year visit in the prompt versus deferred laser groups, there was vision loss of ≥10 letters in 9% versus 8%, an improvement of ≥10 letters in 46% versus 58%, and an improvement of ≥15 letters in 27% versus 38% of participants, respectively. From baseline to 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 versus 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively.
Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment. Although more than half of eyes in which laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years.
To quantify microvasculature changes in the superficial (SCP), middle (MCP), and deep capillary plexuses (DCP) in diabetic retinopathy (DR).
Retrospective cross-sectional study at a tertiary academic ...referral center, in which 26 controls (44 eyes), 27 diabetic subjects without retinopathy (44 eyes), 32 subjects with nonproliferative retinopathy (52 eyes), and 27 subjects with proliferative retinopathy (40 eyes) were imaged with optical coherence tomography angiography (OCTA). Outcome measures included parafoveal vessel density (VD), percentage area of nonperfusion (PAN), and adjusted flow index (AFI) at the different plexuses.
MCP VD and MCP AFI decreased with worsening DR, while PAN increased, mirroring changes within the DCP. The fitted regression line for MCP and DCP AFI were significantly different than the SCP, while DCP PAN differed from SCP PAN with disease progression. Higher SCP AFI and PAN were different in eyes with diabetes without retinopathy compared with controls. Unexpectedly, sex was found to independently influence MCP VD and AFI with worsening disease.
OCTA parameters in the MCP and DCP displayed parallel changes with DR progression, different from the SCP, emphasizing the importance of physiologic considerations in the retinal capillaries. Thus, segmentation protocols that include the MCP within the SCP may be confounded. A difference in DCP PAN with worsening DR was unmasked relative to a prior study that included the MCP with SCP. We confirm that SCP AFI and PAN may serve as early indicators of microvascular changes in DR and identify an interaction between sex and the MCP deserving further study.
Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial.
...Multicenter cohort study.
Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion).
Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit.
Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST).
Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range IQR, 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval CI, 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142-166) and was stable between 2 and 5 years (-1 μm; 95% CI, -12 to 9).
Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.
We quantified retinal and choriocapillaris microvascular changes in healthy control eyes and different stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA).
This ...retrospective cross-sectional study included 137 eyes of 86 patients with different stages of DR and 44 eyes of 26 healthy age-matched controls. Participants were imaged with a commercial OCTA device (RTVue-XR Avanti). We analyzed the superficial (SCP) and deep (DCP) retinal capillary plexus, the full retina, and choriocapillaris for the following OCTA parameters: foveal avascular zone, vessel density, percent area of nonperfusion (PAN), and adjusted flow index (AFI). We adjusted for age, sex, and the correlation between eyes of the same study participant in our statistical models.
All OCTA parameters showed a significant linear correlation with DR severity (P < 0.05) in the univariate models except for AFI measured in the SCP and these correlations remained significant after correcting for covariates. Compared to the other capillary layers, the AFI at the DCP decreased significantly with DR severity. When comparing individual disease severity groups as categories, eyes of subjects with diabetes without DR had significantly increased PAN and AFI in the SCP compared to healthy subjects (P < 0.05).
Retinal and choriocapillaris vascular nonperfusion in OCTA is correlated significantly with disease severity in eyes with DR. Higher flow in the SCP may be an early marker of diabetic microvascular changes before clinical signs of DR. The steep decline of blood flow in the DCP with increasing DR severity suggests that alterations at the DCP warrant further investigation.
To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen.
...Randomized clinical trial.
Six hundred sixty participants with visual acuity (VA) impairment from DME.
Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable.
Change in VA, adverse events, and retreatment frequency.
Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders).
All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.
To describe the features of peripapillary pachychoroid syndrome (PPS), a novel pachychoroid disease spectrum (PDS) entity.
Medical records of 31 eyes (16 patients) with choroidal thickening ...associated with intraretinal and/or subretinal fluid in the nasal macula extending from the disk were reviewed (patients with PPS). Choroidal thickness was compared with 2 age-matched cohorts: typical PDS (17 eyes with central serous chorioretinopathy or pachychoroid neovasculopathy) and 19 normal eyes.
The patients with PPS were 81% men aged 71 ± 7 years. Peripapillary pachychoroid syndrome eyes displayed thicker nasal versus temporal macular choroids, unlike PDS eyes with thicker temporal macular choroids (P < 0.0001). Peripapillary intraretinal and/or subretinal fluid was often overlying dilated Haller layer vessels (pachyvessels). Fundus autofluorescence and fluorescein angiography illustrated peripapillary pigmentary mottling without focal leakage. Most PPS eyes (70%) exhibited other PDS findings including serous pigment epithelial detachment or gravitational tracks. Indocyanine green angiography illustrated dilated peripapillary pachyvessels and choroidal hyperpermeability. The disk was usually crowded, with edema noted in 4/31 (13%) eyes and mild late fluorescein disk leakage identified in half of the cases. Choroidal folds (77%), short axial lengths (39% less than 23 mm), and hyperopia (86%) were common.
Peripapillary pachychoroid syndrome is a distinct PDS variant, in which peripapillary choroidal thickening is associated with nasal macular intraretinal and/or subretinal fluid and occasional disk edema. Recognition of PPS is important to distinguish it from disorders with overlapping features such as posterior uveitis and neuro-ophthalmologic conditions.
Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) are increasingly employed in ophthalmology to reduce miosis and inflammation, manage scleritis, and prevent and treat cystoid macular edema ...associated with cataract surgery. In addition, they may decrease postoperative pain and photophobia associated with refractive surgery and may reduce the itching associated with allergic conjunctivitis. In recent years, the U.S. Food and Drug Administration has approved new topical NSAIDs, and previously approved NSAIDs have been reformulated. These additions and changes result in different pharmacokinetics and dosing intervals, which may offer therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on NSAIDs and a summary of their current uses in ophthalmology with attention to potential future applications.
The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown.
To assess subsequent outcomes of ...eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.
We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit.
Four monthly intravitreous injections of ranibizumab and then as needed per protocol.
Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 μm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (≥2 line) gain or loss of visual acuity among those eyes.
The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.
These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.
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