Differential Response to Anti-VEGF Regimens in Age-Related Macular Degeneration Patients with Early Persistent Retinal Fluid
Glenn J. JaffePeter K. KaiserDesmond ThompsonAndrea GibsonNamrata SarojRobert VittiAlyson J. BerlinerJeffrey S. Heier
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To compare the effect of intravitreal aflibercept or ranibizumab drug type and frequency on visual acuity outcomes in eyes with neovascular age-related macular degeneration (NVAMD) and early persistent retinal fluid after 3 initial monthly injections.A post hoc analysis of eyes enrolled in VIEW 1 and VIEW 2, 2 similarly designed, randomized, phase 3 trials.A total of 1815 eyes with NVAMD from VIEW 1 and VIEW 2.Analyses included patients with known fluid status at baseline and weeks 4, 8, and 12 in 3 treatment groups: ranibizumab 0.5 mg every 4 weeks (Rq4) (n = 595), intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4) (n = 613), and IAI 2 mg every 8 weeks (2q8) after 3 monthly injections (n = 607).Mean best-corrected visual acuity (BCVA) change from baseline over weeks 16 to 52 and the proportion of eyes that gained ≥15 letters or lost ≥5 letters were evaluated in eyes with and without persistent fluid (cystic intraretinal or subretinal fluid at all 4 initial visits). Visual outcomes also were assessed in eyes with persistent fluid by fluid type (intraretinal and subretinal fluid).The proportions of eyes with persistent fluid were 29.4%, 18.8%, and 20.3% in the Rq4, 2q4, and 2q8 groups, respectively. In these eyes, mean BCVA gain from baseline to week 52 was greater with 2q4 compared with Rq4 (P < 0.01) and 2q8 (P < 0.05), whereas it was similar with Rq4 and 2q8 (P = 0.294). At week 52, similar proportions of eyes gained ≥15 letters (31.5%-35.2%), whereas fewer eyes lost ≥5 letters with 2q4 compared with Rq4 and 2q8 (6.5% vs. 16.6% and 16.2%). The pattern of visual outcomes was similar regardless of fluid type. In eyes without persistent fluid, BCVA changes were similar across treatment groups.In patients with early persistent fluid, 2q4 may provide additional clinical benefit over 2q8 or Rq4.Keywords:
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Abstract Given the rising prevalence of patients with diabetes and increasing treatment burden for patients with vision-threatening diabetic macular edema (DME), we aimed to explore the efficacy of modified early intensive and treat-and-extend regimen of anti-vascular endothelial growth factor (VEGF) therapy under the Taiwan National Insurance Bureau reimbursement policy. We obtained data on 69 eyes treated with initial 4-monthly intravitreal injections of aflibercept or ranibizumab, plus individualized treat-and-extend regimen. At 12 months, the mean (SD) change in LogMAR best corrected visual acuity from baseline was − 0.28 (0.31) in all eyes, while that in the aflibercept and ranibizumab groups were − 0.30 (0.34) and − 0.25 (0.28), respectively. Central retinal thickness decreased by 137.2 (122.4) in all eyes, 138.1 (134.2) in the aflibercept group, and 136.2 (110.9) in the ranibizumab group. Additionally, the aflibercept group had a lower mean number of injections than the ranibizumab group (8.5 vs. 8.7). The last extended dosing interval of > 12 weeks was 31.0% and 16.7% of the eyes in the aflibercept and ranibizumab groups, respectively. The modified anti-VEGF regimens effectively managed DME in terms of functional and anatomical outcomes, and efficiently reduced the healthcare burden by reducing the number of injections and extending treatment intervals within 12 months.
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To evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD).We retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid ("good response") was achieved and whether recurrence was observed within 3 months ("dependent") after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA) for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey's test to evaluate the difference between baseline and postinjection VA.Among the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001), and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months.The evaluation of response to and dependence on anti-vascular endothelial growth factor therapies in AMD was useful and practical in managing therapeutic protocols to obtain a good VA.
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Aim
To determine clinical correlations to intraocular vascular endothelial growth factor A (VEGF-A) suppression times (VSTs) on the treatment of neovascular age-related macular degeneration (nAMD) with ranibizumab (Lucentis) or aflibercept (Eylea).Methods
Seven of 89 treatment-naïve nAMD eyes showed persistent choroidal neovascular membrane (CNV) activity throughout a spectral domain optical coherence tomography (SD-OCT)-driven pro re nata (PRN) regimen of intravitreal ranibizumab injections over 28±4 months. The treatment was switched to PRN aflibercept injections and patients were followed for another 15±2 months. A total of 160 aqueous humour specimens were collected before the intravitreal injections, and their VEGF-A concentrations were assayed by Luminex multiplex bead analysis (Luminex, Austin, Texas, USA). Intraocular VEGF-A concentrations were correlated to CNV activity shown by SD-OCT.Results
The mean duration of suppression of VEGF-A concentrations in aqueous humour below the lower limit of quantification of our assay was 34±5 (26–69) days for ranibizumab and 67±14 (49–89) days for aflibercept (p<0.001). The percentual reduction of central retinal volume (CRV) 6 weeks after injection was higher for aflibercept compared with ranibizumab (p=0.009). The time point of clinical re-activity occurred about 50% earlier than the respective VST for each ranibizumab and aflibercept.Conclusions
The VST under aflibercept treatment exceeded that under ranibizumab treatment by a factor of 2. This difference correlated with differential clinical CRV reduction 6 weeks after the respective injection. For both medications, clinical activity was found at a time point as early as 50% of the individual VST.Trial registration number
NCT01213667, post-resultsAflibercept
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To compare the effectiveness of continuous aflibercept versus pro re nata (PRN) ranibizumab therapy for neovascular age-related macular degeneration (nAMD).Multicentre, national electronic medical record (EMR) study on treatment naive nAMD eyes undergoing PRN ranibizumab or continuous (fixed or treat and extend (F/TE)) aflibercept from 21 UK hospitals. Anonymised data were extracted, and eyes were matched on age, gender, starting visual acuity (VA) and year of starting treatment. Primary outcome was change in vision at 1 year.1884 eyes (942 eyes in each group) were included. At year 1, patients on PRN ranibizumab gained 1.6 ETDRS (Early Treatment Diabetic Retinopathy Study) letters (95% CI 0.5 to 2.7, p=0.004), while patients on F/TE aflibercept gained 6.1 letters (95% CI 5.1 to 7.1, p=2.2e-16). Change in vision at 1 year of the F/TE aflibercept group was 4.1 letters higher (95% CI 2.5 to 5.8, p=1.3e-06) compared with the PRN ranibizumab group after adjusting for age, starting VA, gender and year of starting therapy. The F/TE aflibercept group had significantly more injections compared with the PRN ranibizumab group (7.0 vs 5.8, p<2.2e-16), but required less clinic visits than the PRN ranibizumab group (10.8 vs 9.0, p<2.2e-16). Cost-effectiveness analysis showed an incremental cost-effectiveness ratio of 58 047.14 GBP/quality-adjusted life year for continuous aflibercept over PRN ranibizumab.Aflibercept achieved greater VA gains at 1 year than ranibizumab. The observed VA differences are small and likely to be related to more frequent treatment with aflibercept, suggesting that ranibizumab should also be delivered by F/TE posology.
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Aims/Purpose: to report real‐world outcomes in patients with neovascular age‐related macular degeneration (AMD) previously treated with ranibizumab and/or aflibercept and without control of subretinal fluid (SRF) receiving switch treatment to Brolucizumab in Pro Re Nata (PRN) regimen. Methods: Retrospective study including 11 patients with neovascular AMD previously treated with ranibizumab and/or aflibercept and without control of SRF were included. They received intravitreal treatment with standard 6‐mg intravitreal injections of brolucizumab between April 2022 and March 2023 in PRN regimen. Results: The mean follow‐up after the first injection of brolucizumab was 7.25 months (SD 2.18). The mean number of injections per month (IPM) of ranibizumab and/or aflibercept previous to switch treatment to brolucizumab was 0.81 with standard deviation (SD) of 9.81. The mean number of IPM after starting the treatment with brolucizumab was 0.49 (SD: 0.95). Therefore, the amount of IPM was significatively lower when switching to brolucizumab ( p ‐value = 0.0003). SRF control was achieved in 9/11 of patients (81.82%). The mean VA increased from was 0.59/1 (SD 0.273) before switch to brolucizumab to 0.64/1 (SD 0.253) ( p > 0.05). No cases of intraocular inflammation were described. Conclusions: Brolucizumab in PRN regimen was effective in achieving SRF control in patients with neovascular AMD previously treated with ranibizumab and aflibercept and without control of SRF. Furthermore, the amount of IPM was significatively lower when switching to brolucizumab compared to ranibizumab and/or aflibercept.
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Neovascular age-related macular degeneration (nAMD) is treated by intravitreal injections of either ranibizumab, bevacizumab or aflibercept, resulting in stabilization of vision in over 90% of eyes and significant improvement in approximately a third (Seguin-Greenstein et al. 2016). Studies have attempted to identify subgroups of nAMD patients that might benefit more from one agent or another, based on baseline retinal thickness, visual acuity or genetic factors, but no advantage has been reported (Chang et al. 2014). We examined the effect of treatment with aflibercept on best-corrected visual acuity (BCVA) and central retinal thickness (CRT) according to BCVA at the time of treatment switch, in nAMD eyes previously treated with ranibizumab. All eyes had been initially treated for at least 12 months with ranibizumab according to a pro-re-nata (PRN) protocol with monthly clinic visits. Ranibizumab treatment failure was determined as persistent intraretinal or subretinal fluid. Following the switch to aflibercept, (baseline) eyes were treated with three loading injections, every four weeks, followed by additional injections, one every eight weeks. Best-corrected visual acuity (BCVA), measured as ETDRS letters, and CRT were recorded at every follow-up visit. We examined the change in BCVA and CRT during the last 12 months of treatment with ranibizumab as well as during the first 6 months of treatment with aflibercept. A total of 128 eyes of 122 patients were switched from ranibizumab to aflibercept and included in the study. The mean age at baseline was 81 ± 0.75 years, and the mean length of time eyes were treated with ranibizumab was 25.5 ± 1.2 months with an average of 13.5 ± 0.7 injections. For the entire cohort, BCVA at baseline was 20/100 (49.9 ± 2.4 letters) and remained stable at four (20/100, 47.6 ± 2.6 letters, p = 0.63) and six months (20/100, 47.8 ± 2.6 letters, p = 0.5, Fig. 1A). Central retinal thickness (CRT) at baseline was 336.5 ± 11.4 μm, improving at four months (297.7 ± 10.9 μm, p < 0.001) and remaining stable at six months (295.0 ± 12.0 μm, p = 0.006, Fig. 1B). Examining the change in BCVA, we found that in eyes with a baseline BCVA of >20/200, visual acuity improved during the last 12 months of treatment with ranibizumab (+3.6 ± 1.2 letters, p = 0.001, average BCVA 44.6 ± 0.8 letters), but following the switch, this improvement was lost and by four months, they had lost on average −2.0 ± 1.1 letters (p = 0.005, average BCVA 42.8 ± 1.0 letters), remaining stable at 6 months (−2.6 ± 1.1 letters, p = 0.001, average BCVA 42.02 ± 1.11 letters). Conversely, in eyes with a baseline BCVA ≤20/200, visual acuity reduced during the last 12 months of ranibizumab treatment (−2.1 ± 1.3 letters, p = 0.017, average BCVA 19.6 ± 1.2 letters), but increased at four months (+0.9 ± 0.9, p = 0.027, average BCVA 20.4 ± 1.4 letters) and continued at six months following the switch (+1.1 ± 1.0, p = 0.017, average BCVA 20.4 ± 1.5, Fig. 1A). Our findings suggest that there may be a difference in response to treatment with aflibercept based on eyes BCVA at time of switch. While these changes in vision should be regarded as quite modest, the difference in response trends still suggests the entire group of nAMD patients may not be homogenous in regard to response to treatment and that groups of patients will respond in a variable manner to the different drugs. This also supports other studies that have demonstrated that eyes with vision below 20/200 tend to enjoy a greater effect from anti-VEGF treatment (Muniraju et al. 2013). Because our patients were treated with ranibizumab using a PRN protocol, these results might not reflect changes in BCVA if they were being treated on a monthly basis. However, all our patients were treated using the same protocol and the difference in response may still reflect a variable reaction. It is possible that in unresponsive patients, switching to a higher frequency of aflibercept injections would result in a more favourable outcome (Arcinue et al. 2015). Whereas all our patients demonstrated a reduction in CRT following conversion, the visual function did not change accordingly, suggesting that in patients with continued visual deterioration despite anatomical stability, changing agents may be advised to achieve maximal therapeutic effect.
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Introduction This single-center study aimed to compare the 12-month treatment outcomes of ranibizumab with that of aflibercept in routine clinical practice. Methods Cohort of patients diagnosed with treatment-naïve neovascular age-related macular degeneration (AMD), treated using either ranibizumab (n = 33 eyes) or aflibercept (n = 44 eyes) monotherapy over a 12-month follow-up period was analyzed. Anonymous data were extracted from the electronic database dedicated to the drug program. Results In the ranibizumab group, there were no statistically significant changes in best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and central retina thickness (CRT) (µm), between baseline (67.9 ± 8.6 & 384.9 ± 97.9) and at 12 months (67.9 ± 12.1 & 398.9 ± 127.1; P = 0.372 & P = 0.884, respectively). In the aflibercept, there was an improvement in BCVA and reduction in CRT between baseline (64.2 ± 8.1 & 414.3 ± 97.8) and at 12 months (70.7 ± 7.4 & 342.3 ± 71.6; P < 0.001 & P < 0.001, respectively). There was no difference in BCVA between the two groups at either diagnosis (P = 0.101) or 12 months (P = 0.917). Mean number of injections in the ranibizumab group was significantly lower (4.9 ± 1.5) than in the aflibercept group (6.7 ± 1; P < 0.001). Conclusions One initial injection of ranibizumab and then pro re nata (PRN) regimen resulted in stabilization of disease progression. Drug selection and treatment scheme could influence twelve-months outcomes. In the aflibercept group, three initial monthly injections and then every two months provided both significant BCVA improvement and CRT reduction at 12 months of treatment.
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To study visual outcome and number of annual injections in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) before and after a change in first-line therapy from ranibizumab to aflibercept in a high-volume clinical practice.This was a retrospective chart review of routine clinical practice. The study included 1027 treatment-naïve patients, 559 of whom started intravitreal ranibizumab therapy in 2011-2012 and 468 of whom started intravitreal aflibercept therapy in 2013-2014, a fixed loading dose of three injections followed by a pro re nata treatment regimen used in both periods.Snellen best-corrected visual acuity (BCVA) at baseline and after one year was 0.23 and 0.31 (p < 0.0001), respectively, for patients treated with ranibizumab and 0.25 and 0.33 (p < 0.0001) for patients treated with aflibercept, last observation carried forward. The share of patients (73%) still in treatment with ranibizumab at year 1 had a baseline BCVA of 0.26 but 0.40 at year 1 (p < 0.0001), and the patients (75%) still in treatment with aflibercept at year 1 had a baseline BCVA of 0.28 but 0.42 at year 1 (p < 0.0001). Proportional visual gains for both cohorts were comparable for one year (p = 0.14). The number of injections given within year 1 including first injection was 6.9 for ranibizumab and 5.9 for aflibercept (p < 0.0001). In patients continuing treatment through year 1, the number of injections was 8.0 for ranibizumab and 6.6 for aflibercept (p < 0.0001). The two cohorts had similar cause-of-discontinuation profiles.Treatment of nAMD at a single centre in two sequential cohorts yielded comparable BCVA outcomes with 15% fewer injections of aflibercept compared to ranibizumab.
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To compare and report the 2-year treatment outcomes from 3 different anti-VEGF treatment regimens in treating neovascular aged-related macular degeneration (nAMD): Ranibizumab pro re nata (Ranibizumab-PRN); Ranibizumab treat and extend (Ranibizumab-T&E); Aflibercept fixed first year dosing (7 injections) with treat and extend in subsequent year (Aflibercept-Fixed).All treatment-naïve nAMD patients who completed 24 months of monitoring from a single treatment center were included. Patients received the initial loading dose of three injections (4-weekly interval), followed by one of the 3 treatment regimens. Primary outcomes were changes in visual acuity (VA) and central retinal thickness (CRT). Secondary outcome was number of injections required in each year. Data analysis included last observation carried forward (LOCF) for patients with incomplete year-2 follow-up.A total of 249 eyes (230 patients) were studied: 121 Ranibizumab-PRN; 65 Ranibizumab-T&E, and 63 Aflibercept-Fixed. Baseline median VA (ETDRS letters) for Ranibizumab-PRN, Ranibizumab-T&E, and Aflibercept-Fixed was 53.9, 61.1, and 54.9 letters, achieving final VA of 54.9, 65.1, and 65.1 letters, respectively. Hence, the number of letters increased at the end of 24 months for each group was +1.0 (Ranibizumab-PRN), +4.0 (Ranibizumab-T&E), highest +10.2 in Aflibercept-Fixed group. Median number of injections over 2 years (year-1/year-2) was 5/1 for Ranibizumab-PRN, 9/6 for Ranibizumab-T&E, and 7/5 for Aflibercept-Fixed. Both Ranibizumab-T&E and Aflibercept-Fixed also shared the same reduction of median CRT (115 µm), higher than Ranibizumab-PRN (83 µm).We report VA improvement from all three different treatment regimens with both Aflibercept-Fixed and Ranibizumab-T&E regimens achieving the same higher final VA. Aflibercept-Fixed dosing may have more favorable efficacy with the highest VA gain and comparatively lower dosing frequency whereas Ranibizumab-T&E may be more efficient than Ranibizumab-PRN regimen, according to our study.
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To evaluate the efficacy and safety of ranibizumab and aflibercept in the treatment of diabetic macular edema in a real world study, and to compare the two treatments with each other.Retrospective observational study of 213 eyes from 141 patients with diabetic macular edema was completed between June 2014 and June 2016. 122 were treated with ranibizumab intravitreal injection and 91 with aflibercept intravitreal injection, with a loading phase of 3 injections and a Pro Re Nata protocol. The drug was selected by the physician and fluorescein angiography was performed by physician`s criteria. Re-treatment was performed when a decline in BCVA, an increase of central macular thickness or an increase or persistence of intraretinal fluid in OCT was observed. The primary outcome was the mean change in best corrected visual acuity at 1 year, while central macular thickness, central macular volume, the number of injections and visits were evaluated as secondary outcomes. The correlation between BCVA at 4th month visit and BCVA at 12th month visit was also evaluated.The mean baseline best corrected visual acuity for the eyes treated with ranibizumab was 0.55 (+/- 0.35) logMAR, and with aflibercept it was 0.48 (+/- 0.29) (P = 0.109). Best corrected visual acuity improved in both groups, and at the end of the follow-up was 0.40 (+/- 0.35) in the ranibizumab group and 0.40 (+/- 0.29) in the aflibercept group (P = 0.864). Best corrected visual acuity at 4th month visit is correlated at a high value (R = 0.789) with the one at the end of the study. No differences were found in central macular thickness, central macular volume and glycosylated hemoglobin when adjusting with baseline values. The overall number of injections was 5.77 (+/- 2.01), being 5.56 (+/- 2.0) in the ranibizumab group and 6.07 (+/- 1.99) in the aflibercept group (P = 0.069). The main outcome determining final best corrected visual acuity was the baseline best corrected visual acuity (P<0.001).There are no differences in efficacy between ranibizumab and aflibercept in diabetic macular edema treatment in this real world study.
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