Anti-VEGF in the Treatment of Retinal Disease:
Bringing Long-term, Real-world Outcomes into Focus
A report from the 2017 Annual Meeting of the Association for Research in Vision and Ophthalmology
Baltimore, Maryland May 7–11, 2017
By PETER J. KERTES, MD, CM, FRCSC
Long established as a landmark change in the management of neovascular (‘wet’) age-related macular degeneration (AMD), inhibitors of vascular endothelial growth factor (VEGF) continue to accumulate real-world evidence of their benefit to patients with AMD and to macular edema as a result of several conditions. This issue of Ophthalmology Scientific Update highlights several posters and oral presentations from the 2017 annual meeting of the Association for Research in Vision and Ophthalmology that not only discuss these real-world data but also new information on long-term effects of anti-VEGF agents, dosing regimens, and other issues in wet AMD.
Real-world Experience: Outcome Comparisons
Kertes et al presented interim results from the Canadian Treat and Extend Analysis Trial With Ranibizumab (CAN-TREAT), a 24-month, prospective, randomized, open-label, multicentre study comparing the effectiveness of ranibizumab 0.5 mg given in a treat-and-extend (TAE) regimen to monthly dosing in treatment-naïve patients with neovascular age-related macular degeneration (AMD). Of the 580 patients enrolled, 12- and 24-month data were available for 488 (TAE group=251) and 293 (TAE group=148), respectively, as of May 2, 2017. Overall, gains in visual acuity (VA) were similar: +8.3 and +6.1 letters at 12 months in the TAE and monthly groups, respectively, and +6.6 letters and +6.4 letters at 24 months, respectively, which satisfied the noninferiority margin of -5 best corrected (BC) VA letters. Figure 1 shows the mean change in BCVA at 12 and 24 months. The TAE group received an average of 18.3 injections compared to 23.5 injections in the monthly group over the 24-month follow-up. Thus, the investigators found that the TAE regimen was associated with clinically meaningful improvement in BCVA despite fewer ranibizumab injections and physician visits than a monthly dosing schedule.
Figure 1: CAN-TREAT: mean best corrected visual acuity (BCVA) improvement at 12 and 24 months for the treat-and-extend (TAE) and monthly ranibizumab regimens
ETDRS = Early Treatment Diabetic Retinopathy Study
A comparison of VA outcomes at 12 months between ranibizumab and aflibercept was performed using observational data of 394 eyes with neovascular AMD from the Fight Retinal Blindness registry. Ranibizumab-treated eyes gained 3.7 letters, while aflibercept-treated eyes gained 4.3 letters from baseline to 12 months; neither the difference in change in crude VA nor in adjusted mean VA were statistically significant. There was, likewise, no difference in mean number of injections or visits or in the adjusted proportion of eyes with inactive choroidal neovascularization (CNV). Despite these similarities, significantly more patients were switched from ranibizumab to aflibercept (13.7%) than vice versa (3.0%; P<0.001). In both groups, the rate of 12-month treatment completion was approximately 77%.
Outcomes at 36 months were presented from the ASSESS study, in which patients previously treated with bevacizumab and/or ranibizumab were started on fixed-dose aflibercept. Data through 24 months have been previously published.[4,5] The change to a fixed-dose interval showed both anatomic (central subfield thickness [CST]) and visual (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) benefit at 24 months; however, the investigators reported a nonsignificant decline in ETDRS (5 letters; P=0.18) and nonsignificant thickening of CST (+11.95; P=0.18) between months 24 and 36. No predictive factors were identified for changes in BCVA and CST and no serious adverse events were reported in the third year of study. Additional real-world data on aflibercept were provided from the PERSEUS and RAINBOW studies.[6,7] The objective of PERSEUS, conducted in 66 German clinics (N=942), was to investigate the effect of aflibercept and treatment patterns in 2 subgroups of wet AMD patients: treatment-naïve and those who had received any pretreatment. According to the 12-month interim results, mean VA in the treatment-naïve group improved by 5.3±17.4 letters, but pretreated patients experienced a slight (-0.1±15.6 letters) decrease. The investigators determined that treatment regularity had a significant effect on VA outcomes; treatment-naïve and pretreated patients experienced increases in VA of 30.9% and 10.9%, respectively, when treatment was administered regularly, while VA changes were 18.7% and -2.3%, respectively, with irregular treatment. According to a comparison by Framme et al of the PERSEUS and RAINBOW studies, whose baseline patient characteristics were nearly identical, overall 12-month increases of >15 letters with aflibercept treatment were achieved by 27.7% and 25.2% of PERSEUS and RAINBOW patients, respectively, including 32.0% and 28.9%, respectively, of patients receiving regular dosing.
The French ELOUAN 2 registry provided real-life outcomes in an elderly population (N=109; mean age 78.4 years) treated with as-needed (PRN) ranibizumab over 5 years. The investigators found that vision initially improved by 4.2±15.2 letters (P=0.03) but declined thereafter until the end of the 60-month follow-up, at which time the average change in VA was -25.7 letters. Mean number of control visits and injections also continued to decrease through Month 48. The United Kingdom (UK) Aflibercept Users Group, however, suggest that even very elderly patients (>90 years old) can benefit from treatment with vascular endothelial growth factor (VEGF) inhibition. In their study, mean improvements in vision from baseline to 52 weeks were +4.5 letters in Group A (≤90 years; n=8588) and +4.1 letters in Group B (≥91 years; n=739). The percentage of eyes gaining >15 letters was similar: 19.2% in Group A and 17.6% in Group B during Year 1, increasing to 20.5% and 23.1% in Year 2, respectively. The proportions of eyes losing ≥15 letters from baseline at Year 1 and Year 2 were 7.7% and 13.0%, respectively, for Group A and 6.1% and 14%, respectively, for Group B.
Another real-world German observational study, OCEAN, evaluated the impact and use of ocular coherence tomography (OCT) to guide retreatment in wet AMD among 3631 wet AMD patients receiving ranibizumab 0.5 mg. The mean number of injections at 12 months was 4.5 and 3.8 OCT scans were performed; at 24 months, 5.7 injections were given and 5.9 OCT examinations performed. The mean BCVA and change in BCVA at Month 12 were maintained over 24 months. The investigators found a trend towards greater VA improvement with increasing frequency of OCT imaging.
Long-term Outcomes With Anti-VEGF Agents for Neovascular AMD
Two studies involving patients from the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) investigated the long-term impact of anti-VEGF therapy and potential factors in these outcomes. Martin et al reported 5-year follow-up data for 647 subjects, of whom 7.1% were classified as having “good visual acuity (VA) / no treatment,” defined as a median VA of 20/25 at Year 5. The investigators identified several baseline factors associated with a greater probability of this classification, including younger age, improved VA in the study eye, blocked fluorescence associated with a CNV lesion, absence of late AMD in the fellow eye, and no OCT evidence of elevation of the retinal pigment epithelium (RPE). Between years 2 and 5 there was an overall 11-letter loss in VA for the entire cohort. Another multivariate analysis of the CATT data identified factors that were found to be significant predictors of 5-year VA outcomes. Worse baseline VA was significantly associated with worse final VA, more VA gain, higher percentage of a ≥3-line gain, and higher percentage of VA ≤20/200 at 5 years (P<0.001 for all; Table 1). Female sex, bevacizumab treatment in the first 2 years, and absence of RPE elevation were associated with a higher percentage of a ≥3-line gain, and cigarette smoking was associated with a higher percentage with VA ≤20/200.
Table 1: Multivariate analysis for predictors of VA score and VA change from baseline at 5 years
SE = standard error; CNV = choroidal neovascularization
A long-term analysis of response to aflibercept in 722 initially treatment-naïve eyes from the UK Aflibercept Users Group found that only 34.1% completed 3 years of follow-up. Among this cohort, the percentage of patients achieving >70 letters improved from 18.5% at baseline to 32% at 3 years, and 26% gained ≥15 letters. However, the percentage of patients experiencing loss of ≥15 letters increased over the same time period: 4.5% at Year 1, 11.5% at Year 2, and 14.7% at Year 3. The mean number of injections also decreased, from 6.9 in Year 1 to 4.1 in Year 2 and 4.0 in Year 3.
Debate persists about the most efficacious anti-VEGF regimen between monthly and TAE dosing. A meta-analysis involving 4 TAE studies (LUCAS, TREX-AMD, Abedi et al, Oubraham et al), 5 monthly treatment studies (ANCHOR, MARINA, CATT, IVAN, VIEW), 2 quarterly treatment studies (PIER, EXCITE), and 6 PRN treatment studies (PRONTO, SAILOR, SUSTAIN, HARBOR, CATT, IVAN) concluded that TAE was associated with the highest 12-month mean letter gain (9.4 versus 8.7 for monthly injection, 6.2 for PRN, and 1.8 for quarterly) and a mean of 3.1 fewer injections than the monthly regimen (Figure 2).
Figure 2: Letters gained at 12 months by anti-vascular endothelial growth factor (VEGF) dosing regimen
Noninferiority of TAE to monthly injection was also determined in the Phase IIIb TREND study, which compared TAE with monthly dosing of ranibizumab 0.5 mg in 650 treatment-naïve patients aged ≥50 years. Over the 12-month study period, change in BCVA was +6.2 letters for TAE and +8.1 letters for monthly dosing (Figure 3). The TAE regimen was associated with approximately 2.5 fewer injections than monthly dosing. A retrospective, observational clinical study evaluated treatment-naïve patients who received intravitreal aflibercept in a modified TAE (n=37) regimen, where patients are treated until exudative activity disappears and then observed until recurrence, or PRN (n=39) dosing regimen. In the modified TAE group, the mean BCVA improved significantly at 24 months compared with baseline, and was maintained (losing <0.3 LogMAR) in 91.9% of patients over 24 months. In the PRN group, the mean BCVA improved significantly at 6 months and then declined at 12 and 24 months; however, BCVA was maintained at 24 months in 89.8% of patients. Both central retinal and central choroidal thickness (CRT and CCT) decreased significantly from 3 months to 24 months compared with baseline. Mitchell et al compared outcomes from the TAE arm of the TREND study (n=323) to those of an Australian wet AMD cohort (N=227) from the ongoing LUMINOUS trial who received TAE ranibizumab in a real-world setting. Mean VA gains after 12 months were 6.6 and 5.3 ETDRS letters, with an average 8.7 and 7.9 ranibizumab injections, in the TREND and LUMINOUS cohorts, respectively. Good vision (≥73 letters, VA 20/40) was achieved by 45.0% of patients in TREND and 32.3% in LUMINOUS. The authors noted their interim 3-year analysis of the LUMINOUS data “confirmed the generalizability of the TREND clinical trial results.”
Figure 3: TREND: Mean change in BCVA from baseline to end of study
Another analysis from the UK Aflibercept Users Group found that early intervention with more intensive therapy can yield better outcomes if close monitoring and re-treatment are applied regularly. The investigators evaluated patients receiving ≥9 aflibercept injections in the first 56 weeks of treatment. Mean VA at Week 104 was 62.3±17.2 letters, a 6-letter gain from baseline. The mean number of injections in Year 2 was 6.7 (range 0-12), with 26.8% of eyes receiving ≤5 injections. At the Year 2 visit, a VA gain from baseline of ≥15 letters was observed in 28.4% of all eyes, 3.4% lost ≥15 letters from baseline, and 44.4% of eyes achieved ≥70 letters.
Undertreated patients may have worse VA outcomes than patients who undergo fixed treatment intervals, according to a single-centre analysis of treatment-naïve patients who received aflibercept for at least 1 year. The investigators compared changes in VA between patients treated with <8 and with ≥8 aflibercept injections in the first year (n=22 and 20, respectively). Within-group VA change at 12 months was significant for eyes receiving ≥8 injections (+6.0 letters; P=0.026) but not for eyes receiving < 8 injections (+2.7 letters; P=0.196). Outcomes here are similar to VIEW 1 and 2.[20,21] Babalola et al presented a comparison of fixed-dose versus PRN dosing with aflibercept in 100 consecutive treatment-naïve eyes. In the first year, a fixed-dose regimen was adhered to with 3 monthly loading doses and a bimonthly regimen thereafter. During years 2 and onward, a PRN dosing regimen was followed. Over a mean follow-up of 142.9 weeks, the average number of injections was 11 (range, 7-22). The percentage of patients with a >15-letter gain from baseline to Year 1 was 20% but fell to 7% from Year 1 to last follow-up. The percentage of patients experiencing a >15-letter loss from baseline to Year 1 was 8% and increased to 21% from Year 1 to final follow-up. The same group evaluated the change in central macular thickness (CMT) in patients <60 years old with CNV membrane (CNVM) due to AMD, myopic CNVM, and secondary CNVM. The average changes in VA from baseline to final follow-up were 61 to 62.1 letters (AMD-related CNVM), 62.8 to 60 letters (myopic CNVM) and 69 to 60 letters (secondary CNVM). On average, patients received 8.5 injections. There was significant reduction in the CMT, from a baseline of 427 µm to 339 µm at final follow-up. More than one-third (37.9%) were dry on final
Rahimy reported on a subgroup analysis of patients enrolled in VIEW20 who only received injections at
≥12-week intervals compared to patients who received at least one injection at <12-week interval.
Mean BCVA gains achieved at Week 52 in both subgroups were largely maintained (Table 2).
Table 2: Mean VA gains from baseline
Rq4 = 0.5 mg ranibizumab every 4 weeks; 2q4 = 2mg aflibercept every 4 weeks; 2q8 = 2 mg aflibercept every 8 weeks following 3 monthly injections; q12w = every 12 weeks
Two companion papers retrospectively analyzed data from electronic medical records of 100 treatment-naïve eyes to determine the cost effectiveness of anti-VEGF treatments. Almuhtaseb et al reported on 2 groups: Group A (n=51) received aflibercept q8w as per the VIEW modified protocol; Group B (n=49) received TAE ranibizumab. Group A improved by 7.5 letters (P=0.0010), Group B by 8.3 letters (P<0.0001). Mean number of injections was 7 in Group A and 7.75 in Group B (P<0.0001); additional clinic visits beyond those for injections were 3 and 5.75, respectively (P=0.0001). Total mean cost per patient per year was £6919 (CDN $11 604) for aflibercept and £7395 (CDN $12 402) for ranibizumab. In the other paper, Michaels et al reported on eyes that were classified as inactive-dry or active-wet after Year 1 and assigned to 1 of 4 treatment regimens for Year 2. Group A (n=30, wet macula) received intravitreal injections q8w with only 2 follow-up visits at months 17 and 23. The dry macula group received aflibercept in 2 ways: injections capped at 12-week intervals in conjunction with bimonthly OCTs (Group B, n=25) or by TAE (Group C, n=23). In a separate subgroup of wet macula, aflibercept was administered at a greater frequency q6w/q4w in Year 2 (Group D, n=27). Baseline VA and CRT were comparable between Groups A-C, and LogMAR improvement between the 3 groups was comparable at the end of Year 1: 0.45, 0.54, and 0.50 (corresponding to +9, +6, +7 letters), respectively. In Group D, there was no significant change in VA or CRT. Shortening the interval between aflibercept injections to every 6 weeks did not correlate to better clinical outcomes.
Intraocular Pressure (IOP)
A concern with long-term anti-VEGF injections is the possibility of a change in IOP. Atchinson et al evaluated data from 23 873 patients in the IRIS Registry with AMD, diabetic macular edema (DME) or branch or central retinal vein occlusion (BRVO/CRVO) with retinal edema who received ≥1 anti-VEGF injection during the 3-year study period. The mean age of patients was 76 years and mean follow-up was 681 days. Of this total study population, subgroups included (but were not limited to) those with AMD only as well as patients who were treatment-naïve for ≥1 year before the start of the study (“new”). All subgroups experienced changes in IOP, with IOP changes higher in those receiving bevacizumab, although the differences between the groups was small, suggesting no clinically relevant difference between anti-VEGF treatments.
A secondary analysis of the CATT data[28,29] suggests that medications that lower IOP by decreasing fluid production in the eye may help to improve outcomes in wet AMD patients who are being treated with anti-VEGF injections. Hsu et al analyzed patients in CATT who were also on a prostaglandin analogue (Group A; n=28), a topical beta-blocker (Group B; n=19), or on no IOP-lowering drugs (Group C; n=857); the group excluded patients on multiple glaucoma medications or those on a-agonists alone. Letter gains at 2 years were 3.5 for Group A, 13.8 for Group B, and 6.3 for Group C; the difference in letter gain between Groups B and C neared statistical significance (P=0.052). When Group B was 1:1 matched to controls, mean VA change was +13.8 letters in Group B versus +1.9 letters in matched controls (P=0.04), mean retinal thickness change was -106 µm versus -44 µm (P=0.33), and mean total thickness change was -251 µm versus -228 µm (P=0.38). Aqueous suppressants “may have an influence” on both retinal thickness and VA outcomes in those with AMD, but Dr. Hsu urged caution with these results, adding that Wills Eye Hospital, Philadelphia, is currently conducting a randomized prospective study on the addition of dorzolamide-timolol topical drugs to those undergoing treatment for AMD with anti-VEGF agents.
The effectiveness and safety of anti-VEGF agents in the management of patients with AMD and other conditions involving macular edema that was demonstrated in clinical trials is increasingly supported by emerging real-world and long-term evidence. Additional studies are improving our understanding of the factors that contribute to disease worsening, and data show no significant loss in effectiveness with the use of injection-reducing regimens.
Dr. Kertes is Professor, Department of Ophthalmology and Vision Sciences, University of Toronto, and the Ophthalmologist-in-Chief, Sunnybrook Health Sciences Centre, Toronto, Ontario.
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Disclosure: Dr. Kertes has received research funding from Allergan, Novartis, Regeneron, Bayer, Janssen, Roche, and Allergan, and has received honoraria from Bausch + Lomb, Novartis, Bayer, and Allergan. He is a consultant for Novartis and Bayer, and has shares in ArcticDx. He wishes to thank Michelle Dalton, ELS, for her editorial assistance in the preparation of this manuscript.
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