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Hyperreflective Walls in Foveal Cystoid Spaces as a Biomarker of Diabetic Macular Edema Refractory to Anti-VEGF Treatment.
Terada, N, Murakami, T, Uji, A, Dodo, Y, Mori, Y, Tsujikawa, A
Scientific reports. 2020;(1):7299
Abstract
Diabetic macular edema (DME) refractory to anti-VEGF drugs is a socioeconomic burden. In this retrospective study, we investigated the relationship between DME remission and hyperreflective walls in foveal cystoid spaces, a novel finding on spectral domain optical coherence tomography (SD-OCT) images in DME. In a cross-sectional study, we assessed the relationship between hyperreflective walls in foveal cystoid spaces and other OCT findings in 110 eyes of 110 DME patients. Hyperreflective walls were delineated in 27 of 171 foveal cystoid spaces. Eyes with hyperreflective walls in foveal cystoid spaces had poorer visual acuity and more severe photoreceptor disruption than did those without such findings (P = 0.008 and P < 0.001, respectively). In the other longitudinal study, we evaluated the relationship between this finding and the remission in 54 eyes of 51 DME patients treated with as-needed ranibizumab injections for 24 months. Foveal cystoid spaces with hyperreflective walls were often persistent, and the cumulative rates of DME remission among eyes with and without the hyperreflective walls were 7.7% (1 eye) and 48.8% (20 eyes) at 18 months (hazard ratio, 0.092; P = 0.025). We characterized hyperreflective walls in foveal cystoid spaces and designated them as a predictor of no DME remission under ranibizumab injections.
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Intravitreal ranibizumab for persistent diabetic vitreous haemorrhage: a randomised, double-masked, placebo-controlled feasibility study.
Petrarca, R, Soare, C, Wong, R, Desai, R, Neffendorf, J, Simpson, A, Jackson, TL
Acta ophthalmologica. 2020;(8):e960-e967
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PURPOSE To determine the feasibility of a definitive study of intravitreal ranibizumab to promote the clearance of persistent diabetic vitreous haemorrhage and thereby avoid vitrectomy. METHODS This randomised, double-masked, placebo-controlled feasibility study recruited 24 participants with persistent diabetic vitreous haemorrhage listed for pars plana vitrectomy. Participants were randomised to a single 0.5-mg intravitreal ranibizumab injection or a single subconjunctival saline injection. The primary outcome measure was the number of participants requiring pars plana vitrectomy at week 7. RESULTS Eight of 12 participants (66.7%) in the ranibizumab group required vitrectomy at week 7 versus 12 of 12 (100%) in the placebo group (absolute risk reduction 33.3%, 95% confidence interval 2.1-70.7%; p = 0.09). One additional eye in the ranibizumab group required vitrectomy by 12 months. Mean visual acuity letter score at 12 months was 72.7 ± 12.3 in the ranibizumab group and 75.1 ± 10.1 in the placebo group. Safety was similar across groups. CONCLUSION Intravitreal ranibizumab may reduce the likelihood of proceeding to vitrectomy in patients with persistent, dense diabetic vitreous haemorrhage. Further studies appear feasible and justified.
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Bimonthly, treat-and-extend and as-needed ranibizumab in naïve neovascular age-related macular degeneration patients: 12-month outcomes of a randomized study.
López Gálvez, MI, Arias Barquet, L, S Figueroa, M, García-Layana, A, Ruiz Moreno, JM, ,
Acta ophthalmologica. 2020;(7):e820-e829
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PURPOSE To assess the noninferiority of the treat-and-extend (T&E) and fixed bimonthly regimens of 0.5 mg intravitreal ranibizumab as compared with the pro re nata (PRN) in naïve patients with neovascular age-related macular degeneration (nAMD). METHODS Phase IV, randomized, 12-month, multicentre trial. Patients aged ≥50 years with nAMD and visual impairment [best-corrected visual acuity (BCVA) between 23 and 78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] were eligible. Patients (one eye per patient) were randomized to bimonthly, n = 103, T&E, n = 99 or PRN, n = 104. Noninferiority was established at five letters ETDRS. RESULTS The mean (95% CI) difference in BCVA at 12 months was 7.2 (4.2-10.2), 6.4 (2.9-9.8), and 8.0 (51.1-11.0) in the bimonthly, T&E and PRN, respectively. The bimonthly or T&E regimens were not inferior to the PRN scheme. All regimens were associated with a significant reduction of central subfield thickness and volume. The mean (95% CI) number of injections in the bimonthly regimen (7.6, 7.5-7.7) was similar as compared with the PRN regimen (7.4, 6.7-8.0) (p = 0.159) but lower than in the T&E regimen (9.3, 8.9-9.7) (p < 0.001). CONCLUSION At 12 months, bimonthly and T&E ranibizumab were noninferior to PRN in naïve nAMD.
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Spectral-Domain OCT Predictors of Visual Outcomes after Ranibizumab Treatment for Macular Edema Resulting from Retinal Vein Occlusion.
Yiu, G, Welch, RJ, Wang, Y, Wang, Z, Wang, PW, Haskova, Z
Ophthalmology. Retina. 2020;(1):67-76
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PURPOSE To evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE). DESIGN Post hoc analysis of prospective clinical trial data. PARTICIPANTS Two hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema. METHODS Baseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections. MAIN OUTCOME MEASURES Association of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections. RESULTS Before therapy, worse baseline BCVA was associated with ERM presence (P = 0.0045), thicker SRF (P = 0.0006), larger intraretinal cysts (P = 0.0015), and higher percentage of DRIL (P < 0.0001), percentage of ELM disruption (P < 0.0001), percentage of EZ disruption (P = 0.0003), and percentage of IZ disruption (P = 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P < 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P < 0.0001) and worse baseline BCVA (P < 0.0001). CONCLUSIONS Although SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements.
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Long-Term Vision Outcomes in Patients With DME and a Limited Early Visual Response to Ranibizumab in RIDE and RISE.
Singh, RP, Pieramici, DJ, Wang, PW, Gune, S
Ophthalmic surgery, lasers & imaging retina. 2020;(4):210-218
Abstract
BACKGROUND AND OBJECTIVE To compare early and long-term visual responses to ranibizumab in patients with diabetic macular edema. PATIENTS AND METHODS Retrospective analysis of RIDE (NCT00473382) and RISE (NCT00473330). Vision outcomes over 36 months were compared between limited early gainers (gained ≤ 5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), early 1-line gainers (gained 6 to 9 ETDRS letters), and early 2-or-more-line gainers (gained ≥ 10 ETDRS letters) at Month 3. RESULTS Among 235 ranibizumab-treated patients, 42.6%, 20.0%, and 37.4% were limited early gainers, early 1-line gainers, and early 2-or-more-line gainers, respectively. At Month 36, 71.3% of limited early gainers achieved 6 to 9 and 10 or more ETDRS letter gains. Mean ETDRS letter scores at Month 36 were comparable between limited early gainers (67.8), early 1-line gainers (73.4), and early 2-or-more-line gainers (71.6). CONCLUSION Clinically meaningful vision outcomes were achieved with long-term ranibizumab treatment, irrespective of early visual acuity response. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:210-218.].
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Short-time effect of intravitreal injections on retinal vascular oxygenation and vessel diameter in patients with diabetic macular oedema or neovascular age-related macular degeneration.
Mitsch, C, Pemp, B, Pollreisz, A, Gleiss, A, Karst, S, Scholda, C, Sacu, S, Schmidt-Erfurth, U
Acta ophthalmologica. 2020;(3):e301-e308
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PURPOSE To investigate the short-time effect of intravitreal injections (IVI) of the vascular endothelial growth factor inhibitors ranibizumab and aflibercept on retinal arterial and venous oxygen saturation (SO2a and SO2v), arteriovenous oxygen saturation difference (AVD) and vessel diameter (VDa and VDv) in patients with diabetic macular oedema (DME) and patients with choroidal neovascularization (CNV) due to age-related macular degeneration. METHODS Uncontrolled prospective observational study in 100 eyes. Retinal vessel oxygen saturation and diameters were assessed using a retinal oximeter before and minutes after IVI of ranibizumab or aflibercept. RESULTS 40 eyes with CNV and 34 eyes with DME were included in the analysis. At baseline, SO2a and SO2v were significantly higher in DME (p = 0.043 and p = 0.009, respectively). After IVI, SO2a significantly decreased in CNV and DME eyes by 2.6% (p = 0.016) and 4.6% (p = 0.002) and SO2v decreased by 14.0% (p = 0.004) and 12.4% (p = 0.017), respectively. However, a significant increase in AVD was only found in CNV (15.7%, p = 0.001). VDa decreased significantly only in DME by 5.7% (p = 0.010). No medication-specific disease effect was found and vice versa. CONCLUSIONS The observed changes can be interpreted as signs of increased metabolic demand during the physiological stress after an IVI. The abnormal arterial constriction and the abolished increase in AVD seen only in eyes with DME indicate an impairment of vascular autoregulation and oxygen distribution and a reduced neuroretinal metabolism in the diabetic retina with a significant impact on inner retinal oxygen consumption shortly after IVI.
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Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study.
Shimura, M, Kitano, S, Muramatsu, D, Fukushima, H, Takamura, Y, Matsumoto, M, Kokado, M, Kogo, J, Sasaki, M, Morizane, Y, et al
The British journal of ophthalmology. 2020;(12):1755-1761
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BACKGROUND/AIMS: To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). METHODS Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. RESULTS Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. CONCLUSION For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.
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Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial.
Khanani, AM, Patel, SS, Ferrone, PJ, Osborne, A, Sahni, J, Grzeschik, S, Basu, K, Ehrlich, JS, Haskova, Z, Dugel, PU
JAMA ophthalmology. 2020;(9):964-972
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IMPORTANCE Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding. OBJECTIVE To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration. DESIGN, SETTING, AND PARTICIPANTS This phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018. INTERVENTIONS Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks. MAIN OUTCOMES AND MEASURES Mean change in BCVA from baseline at week 40. RESULTS Of 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified. CONCLUSIONS AND RELEVANCE At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03038880.
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SIERRA-AMD: A Retrospective, Real-World Evidence Study of Patients with Neovascular Age-Related Macular Degeneration in the United States.
Khanani, AM, Skelly, A, Bezlyak, V, Griner, R, Torres, LR, Sagkriotis, A
Ophthalmology. Retina. 2020;(2):122-133
Abstract
PURPOSE Characterize real-world baseline visual acuity (VA) and anti-vascular endothelial growth factor (VEGF) treatment patterns in neovascular age-related macular degeneration patients in 2012-2015. DESIGN Retrospective, multicenter, noninterventional real-world evidence study. PARTICIPANTS A total of 98 821 eyes from 79 885 patients receiving intravitreal anti-VEGF therapy. METHODS Anonymized patient data routinely collected over 5 years were extracted from 58 United States centers to a central database using an electronic medical records system. MAIN OUTCOME MEASURES Baseline VA, VA change from baseline, treatment frequencies, annual anti-VEGF injections, bilateral treatment frequencies, annual total clinic visits, and noninjection clinic visits. RESULTS Baseline characteristics were comparable across years. Baseline VAs (Mean±standard deviation [SD] Early Treatment Diabetic Retinopathy Study [ETDRS] letters) were similar for 2012, 2013, and 2014 (53.6±23.3, 53.2±23.4, and 53.1±23.6, respectively), but was lower for 2015 (50.7±24.4). In eyes with 4-year follow-up, VA changes from baseline (ETDRS letters) were least squares means of +1.1 (95% confidence interval [CI], 1.0;1.3), -1.3 (95%CI, -1.5;-1.0), and -3.1 (95%CI, -3.5;-2.7), and -5.2 (95%CI, -6.0;-4.3) for years 1-4. Mean±SD number of injections was 7.5±1.9, 6.7±2.1, 6.6±2.3, and 6.4±2.3 for years 1-4. By year 4, 36.7% of eyes had ≤8-week dosing intervals (q8w) and 21.2% had ≥12-week dosing intervals. Eyes treated q8w increased 40% from Year 1 (32.4%) to Year 4 (45.3%). Baseline bilateral treatment frequency was 6.1%. Of the patients treated bilaterally, 32.0% received the first treatment in the better-seeing eye, and 68.0% received first treatment in an eye with vision the same as or worse than the fellow-eye. This trend was evident across all index years. CONCLUSIONS This real-world study describes the treatment burden, initiation and monitoring patterns, and VA outcomes at a scale and timeframe that has not been previously reported. In this cohort, baseline VA was similar for the index years 2012-2014, but lower for 2015. In patients with 4-year follow-up, both VA and injection frequency declined, whereas the proportion of eyes treated more frequently than the recommended q8w interval increased. The reduction in dosing intervals may be a consequence of intensification of treatment due to year-on-year VA loss and disease progression.
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Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial.
Sahni, J, Dugel, PU, Patel, SS, Chittum, ME, Berger, B, Del Valle Rubido, M, Sadikhov, S, Szczesny, P, Schwab, D, Nogoceke, E, et al
JAMA ophthalmology. 2020;(9):955-963
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IMPORTANCE Faricimab, the first bispecific antibody designed for intraocular use, simultaneously and independently binds and neutralizes angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). OBJECTIVE To assess the efficacy and safety of different doses and regimens of faricimab vs ranibizumab in patients with neovascular age-related macular degeneration (nAMD). DESIGN, SETTING, AND PARTICIPANTS AVENUE was a 36-week, multiple-dose-regimen, active comparator-controlled, double-masked, phase 2 randomized clinical study performed at 58 sites in the United States. Eligible participants were anti-VEGF treatment naive with choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 73 (Snellen equivalent, 20/40) to 24 (Snellen equivalent, 20/320). Data were collected from August 11, 2015, to January 12, 2017, with the final patient visit completed September 26, 2017. Data were analyzed from August 11, 2015, to October 4, 2019. INTERVENTIONS Patients were randomized 3:2:2:2:3 to receive ranibizumab, 0.5 mg every 4 weeks (arm A [n = 68]); faricimab, 1.5 mg every 4 weeks (arm B [n = 47]); faricimab, 6.0 mg every 4 weeks (arm C [n = 42]); faricimab, 6.0 mg every 4 weeks until week 12, then faricimab, 6.0 mg every 8 weeks (arm D [n = 47]); and ranibizumab, 0.5 mg every 4 weeks until week 8, then faricimab, 6.0 mg every 4 weeks (arm E [n = 69]). MAIN OUTCOMES AND MEASURES Mean change in BCVA from baseline to week 36, proportion of participants gaining at least 15 letters, BCVA of 20/40 or better or 20/200 or worse, and ocular coherence tomographic outcomes in anti-VEGF treatment-naive participants (arms A, B, C, D) and from weeks 12 to 36 in those with incomplete response (participants in arms A and E with week 12 BCVA ETDRS letter score of ≤68 [Snellen equivalent, 20/50 or worse]). RESULTS A total of 263 participants were included in the analysis (172 [65.4%] female; 258 [98.1%] white; mean [SD] age, 78.3 [8.7] years). At week 36, adjusted mean change in BCVA vs ranibizumab was 1.6 (80% CI, -1.6 to 4.7) letters for arm B (P = .52), -1.6 (80% CI, -4.9 to 1.7) letters for arm C (P = .53), and -1.5 (80% CI, -4.6 to 1.6) letters for arm D (P = .53). For arm E, adjusted mean change from week 12 was -1.7 (80% CI, -3.8 to 0.4) letters (P = .30). CONCLUSIONS AND RELEVANCE AVENUE did not meet its primary end point of superiority of faricimab over ranibizumab in BCVA at week 36. Although not superior to monthly ranibizumab as given in this trial, overall visual and anatomical gains noted with faricimab support pursuing phase 3 trials for a potential alternative to monthly anti-VEGF therapy. Faricimab showed no new or unexpected safety signals. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02484690.