To compare rates and identify predictive factors for events that represent worsening of proliferative diabetic retinopathy (PDR) in eyes treated with panretinal photocoagulation (PRP) or ranibizumab.
...Randomized clinical trial (55 United States sites).
Three hundred ninety-four study eyes from 305 adults with PDR, visual acuity (VA) 20/320 or better, and no history of PRP.
Panretinal photocoagulation or intravitreous ranibizumab injections (0.5 mg/0.05 ml).
Time from randomization to a composite PDR-worsening outcome defined as the first occurrence of vitreous hemorrhage, retinal detachment, anterior segment neovascularization, or neovascular glaucoma.
Through 2 years, the cumulative probability of worsening PDR was 42% (PRP) versus 34% (ranibizumab; hazard ratio HR, 1.33; 99% confidence interval CI, 0.90 to 1.98; P = 0.063). Worse baseline levels of diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study scale) were associated with increased risk of worsening PDR, regardless of treatment group (64% high-risk PDR or worse vs. 23% moderate PDR or better; HR, 3.97; 99% CI, 2.48 to 6.36; P < 0.001). In the PRP group, eyes receiving pattern scan versus conventional single-spot PRP also were at higher risk for worsening PDR (60% vs. 39%; HR, 2.04; 99% CI, 1.02 to 4.08; P = 0.008), regardless of the number of spots placed or the number of sittings to complete the initial PRP. Eyes in both groups with vision-impairing (VA 20/32 or worse) center-involved diabetic macular edema (DME) at baseline were required to receive ranibizumab for center-involved DME. Therefore the composite outcome was compared by treatment in the subgroup of eyes that did not have vision-impairing center-involved DME at baseline. For these eyes, the rate of PDR-worsening was greater with PRP than ranibizumab (45% vs. 31%; HR, 1.62; 99% CI, 1.01 to 2.60; P = 0.008).
In eyes with PDR, ranibizumab resulted in less PDR worsening compared with PRP, especially in eyes not required to receive ranibizumab for center-involved DME. Although anti-vascular endothelial growth factor therapy requires a more frequent visit schedule than PRP, these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through 2 years.
IMPORTANCE: Vitreous hemorrhage from proliferative diabetic retinopathy can cause loss of vision. The best management approach is unknown. OBJECTIVE: To compare initial treatment with intravitreous ...aflibercept vs vitrectomy with panretinal photocoagulation for vitreous hemorrhage from proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 39 DRCR Retina Network sites in the US and Canada including 205 adults with vison loss due to vitreous hemorrhage from proliferative diabetic retinopathy who were enrolled from November 2016 to December 2017. The final follow-up visit was completed in January 2020. INTERVENTIONS: Random assignment of eyes (1 per participant) to aflibercept (100 participants) or vitrectomy with panretinal photocoagulation (105 participants). Participants whose eyes were assigned to aflibercept initially received 4 monthly injections. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity letter score (range, 0-100; higher scores indicate better vision) over 24 weeks (area under the curve); the study was powered to detect a difference of 8 letters. Secondary outcomes included mean visual acuity at 4 weeks and 2 years. RESULTS: Among 205 participants (205 eyes) who were randomized (mean SD age, 57 11 years; 115 56% men; mean visual acuity letter score, 34.5 Snellen equivalent, 20/200), 95% (195 of 205) completed the 24-week visit and 90% (177 of 196, excluding 9 deaths) completed the 2-year visit. The mean visual acuity letter score over 24 weeks was 59.3 (Snellen equivalent, 20/63) (95% CI, 54.9 to 63.7) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) (95% CI, 58.6 to 67.3) in the vitrectomy group (adjusted difference, −5.0 95% CI, −10.2 to 0.3, P = .06). Among 23 secondary outcomes, 15 showed no significant difference. The mean visual acuity letter score was 52.6 (Snellen equivalent, 20/100) in the aflibercept group vs 62.3 (Snellen equivalent, 20/63) in the vitrectomy group at 4 weeks (adjusted difference, −11.2 95% CI, −18.5 to −3.9, P = .003) and 73.7 (Snellen equivalent, 20/40) vs 71.0 (Snellen equivalent, 20/40) at 2 years (adjusted difference, 2.7 95% CI, −3.1 to 8.4, P = .36). Over 2 years, 33 eyes (33%) assigned to aflibercept received vitrectomy and 34 eyes (32%) assigned to vitrectomy received subsequent aflibercept. CONCLUSIONS AND RELEVANCE: Among participants whose eyes had vitreous hemorrhage from proliferative diabetic retinopathy, there was no statistically significant difference in the primary outcome of mean visual acuity letter score over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation. However, the study may have been underpowered, considering the range of the 95% CI, to detect a clinically important benefit in favor of initial vitrectomy with panretinal photocoagulation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858076
IMPORTANCE: Large amounts of optical coherence tomographic (OCT) data of diabetic macular edema (DME) are acquired, but many morphologic features have yet to be identified and quantified. OBJECTIVE: ...To examine the volumetric change of intraretinal fluid (IRF) and subretinal fluid (SRF) in DME during anti–vascular endothelial growth factor treatment using deep learning algorithms. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a randomized clinical trial, the Diabetic Retinopathy Clinical Research Network (protocol T), assessed 6945 spectral-domain OCT volume scans of 570 eyes from 570 study participants with DME. The original trial was performed from August 21, 2012, to October 18, 2018. This analysis was performed from December 7, 2017, to January 15, 2020. INTERVENTIONS: Participants were treated according to a predefined, standardized protocol with aflibercept, ranibizumab, or bevacizumab with or without deferred laser. MAIN OUTCOMES AND MEASURES: The association of treatment with IRF and SRF volumes and best-corrected visual acuity (BCVA) during 12 months using deep learning algorithms. RESULTS: Among the 570 study participants (302 53% male; 369 65% white; mean SD age, 43.4 12.6 years), the mean fluid volumes in the central 3 mm were 448.6 nL (95% CI, 412.3-485.0 nL) of IRF and 36.9 nL (95% CI, 27.0-46.7 nL) of SRF at baseline and 161.2 nL (95% CI, 135.1-187.4 nL) of IRF and 4.4 nL (95% CI, 1.7-7.1 nL) of SRF at 12 months. The presence of SRF at baseline was associated with a worse baseline BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) score of 63.2 (95% CI, 60.2-66.1) (approximate Snellen equivalent of 20/63 95% CI, 20/50-20/63) in eyes with SRF vs 66.9 (95% CI, 65.7-68.1) (approximate Snellen equivalent, 20/50 95% CI, 20/40-20/50) without SRF (P < .001) and a greater gain in ETDRS score (0.5; 95% CI, 0.3-0.8) every 4 weeks during follow-up in eyes with SRF at baseline vs 0.4 (95% CI, 0.3-0.5) in eyes without SRF at baseline (P = .02) when adjusted for baseline BCVA. Aflibercept was associated with greater reduction of IRF volume compared with bevacizumab after the first injection (difference, 79.8 nL; 95% CI, 5.3-162.5 nL; P < .001) and every 4 weeks thereafter (difference, 10.4 nL; 95% CI, 0.7-20.0 nL; P = .004). Ranibizumab was associated with a greater reduction of IRF after the first injection compared with bevacizumab (difference, 75.2 nL; 95% CI, 1.4-154.7 nL; P < .001). CONCLUSIONS AND RELEVANCE: Automated segmentation of fluid in DME revealed that the presence of SRF was associated with lower baseline BCVA but with good response to anti–vascular endothelial growth factor therapy. These automated spectral-domain OCT analyses may be used clinically to assess anatomical change during therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01627249.
IMPORTANCE: 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. OBJECTIVE: To assess ...subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: Four monthly intravitreous injections of ranibizumab and then as needed per protocol. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.
To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S.
Post ...hoc analyses from a randomized clinical trial.
Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP).
Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria.
Neovascularization status through 2 years.
At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years.
The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
IMPORTANCE: Anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) favorably affects diabetic retinopathy (DR) improvement and worsening. It is unknown whether ...these effects differ across anti-VEGF agents. OBJECTIVE: To compare changes in DR severity during aflibercept, bevacizumab, or ranibizumab treatment for DME. DESIGN, SETTING, AND PARTICIPANTS: Preplanned secondary analysis of data from a comparative effectiveness trial for center-involved DME was conducted in 650 participants receiving aflibercept, bevacizumab, or ranibizumab. Retinopathy improvement and worsening were determined during 2 years of treatment. Participants were randomized in 2012 through 2013, and the trial concluded on September 23, 2015. INTERVENTIONS: Random assignment to aflibercept, 2.0 mg; bevacizumab, 1.25 mg; ranibizumab, 0.3 mg, up to every 4 weeks through 2 years following a retreatment protocol. MAIN OUTCOMES AND MEASURES: Percentages with retinopathy improvement at 1 and 2 years and cumulative probabilities for retinopathy worsening through 2-year without adjustment for multiple outcomes. RESULTS: A total of 650 participants (495 76.2% nonproliferative DR NPDR, 155 proliferative DR PDR) were analyzed; 302 (46.5%) were women and mean (SD) age was 61 (10) years; 425 (65.4%) were white. At 1 year, among 423 NPDR eyes, 44 of 141 (31.2%) treated with aflibercept, 29 of 131 (22.1%) with bevacizumab, and 57 of 151 (37.7%) with ranibizumab had improvement of DR severity (adjusted difference: 11.7%; 95% CI, 2.9% to 20.6%; P = .004 for aflibercept vs bevacizumab; 8.9%; 95% CI, 1.7% to 16.1%; P = .01 for ranibizumab vs bevacizumab; and 2.9%; 95% CI, −5.7% to 11.4%; P = .51 for aflibercept vs ranibizumab). At 2 years, 33 eyes (24.8%) in the aflibercept group, 25 eyes (22.1%) in the bevacizumab group, and 40 eyes (31.0%) in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab (adjusted difference: 50.4%; 95% CI, 26.8% to 74.0%; P < .001 for aflibercept vs bevacizumab; 20.4%; 95% CI, −3.1% to 44.0%; P = .09 for ranibizumab vs bevacizumab; and 30.0%; 95% CI, 4.4% to 55.6%; P = .02 for aflibercept vs ranibizumab). These rates and treatment group differences appeared to be maintained at 2 years. Despite the reduced numbers of injections in the second year, 66 (59.5%) of NPDR and 28 (70.0%) of PDR eyes that manifested improvement at 1 year maintained improvement at 2 years. Two-year cumulative rates for retinopathy worsening ranged from 7.1% to 10.2% and 17.2% to 26.4% among anti-VEGF groups for NPDR and PDR eyes, respectively. No statistically significant treatment differences were noted. CONCLUSIONS AND RELEVANCE: At 1 and 2 years, eyes with NPDR receiving anti-VEGF treatment for DME may experience improvement in DR severity. Less improvement was demonstrated with bevacizumab at 1 year than with aflibercept or ranibizumab. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with PDR at baseline. All 3 anti-VEGF treatments were associated with low rates of DR worsening. These data provide additional outcomes that might be considered when choosing an anti-VEGF agent to treat DME.
IMPORTANCE: Understanding measurement variability and relationships between measurements obtained on different optical coherence tomography (OCT) machines is critical for clinical trials and clinical ...settings. OBJECTIVE: To evaluate the reproducibility of retinal thickness measurements from OCT images obtained by time-domain (TD) (Stratus; Carl Zeiss Meditec) and spectral-domain (SD) (Cirrus; Carl Zeiss Meditec, and Spectralis; Heidelberg Engineering) instruments and formulate equations to convert retinal thickness measurements from SD-OCT to equivalent values on TD-OCT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional observational study was conducted in private and institutional practices. Persons with diabetes mellitus who had at least 1 eye with central-involved diabetic macular edema, defined as Stratus central subfield thickness (CST) of 250 μm or greater, participated. An additional normative cohort (individuals with diabetes but without diabetic macular edema) was enrolled. Each study eye underwent 2 replicate Stratus scans followed by 2 replicate Cirrus or Spectralis scans (real-time image registration used) centered on the fovea. MAIN OUTCOMES AND MEASURES: Optical coherence tomography CST and macular volume. RESULTS: The Bland-Altman coefficient of repeatability for relative change in CST (the degree of change that could be expected from measurement variability) was lower with Spectralis (7%) compared with Cirrus (14%) and Stratus (12% and 15% within Cirrus/Stratus and Spectralis/Stratus groups, respectively). For each cohort, the initial Stratus CST was within 10% of the replicate Stratus measurement nearly all of the time; the conversion equations predicted a Stratus CST within 10% of the observed thickness 86% and 89% of the time for Cirrus/Stratus and Spectralis/Stratus groups, respectively, which is similar to the agreement on Stratus test-retest. The Bland-Altman limits of agreement for relative change in CST between machines (the degree of change that could be expected from measurement variability combining within and between instrument variability) were 21% for Cirrus and 19% for Spectralis when comparing predicted vs actual Stratus measurement. CONCLUSIONS AND RELEVANCE: Reproducibility appears to be better with Spectralis than with Cirrus and Stratus. Conversion equations to transform Cirrus or Spectralis measurements to Stratus-equivalent values, within 10% of the observed Stratus thickness values, appear feasible. Central subfield thickness changes beyond 10% when using the same machine or 20% when switching machines, after conversion to Stratus equivalents, are likely due to a change in retinal thickness rather than measurement error.
To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 ...mg ranibizumab for diabetic macular edema (DME).
Multicenter, randomized clinical trial.
Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment.
Best-corrected visual acuity and safety at the 156-week (3-year) visit.
The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4-5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% (P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% (P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively (P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 μm or more on time-domain optical coherence tomography were 36% in both groups (P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups.
These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues.
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