Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Switching Anti-Vascular Endothelial Growth Factors in Refractory Neovascular Age-Related Macular Degeneration

Mohammed Ashraf, FRCOphth; Touka Banaee, MD; Fabiana Q. Silva; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

Anti-vascular endothelial growth factor (VEGF) therapy is the treatment of choice for cases with neovascular age-related macular degeneration (AMD). Switching to an alternate anti-VEGF has been suggested as a possible option for resistant cases. The purpose of this review is to evaluate whether the timing of switching affects treatment outcomes.

PATIENTS AND METHODS:

A review of published literature was performed looking at all studies where patients with refractory neovascular AMD were switched to an alternative anti-VEGF. Studies were then stratified based on the timing of switching into early (< 12 previous injections) and late (> 12 previous injections).

RESULTS:

A total of 38 studies were identified: 18 where patients were switched early and 20 where they were switched late. Both subgroups showed anatomic improvement after switching, with limited visual gains.

CONCLUSION:

There are insufficient data to recommend early versus late switching. However, both groups showed a reduction of fluid on optical coherence tomography and visual gains in 25% to 30% of patients.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:166–170.]

Abstract

BACKGROUND AND OBJECTIVE:

Anti-vascular endothelial growth factor (VEGF) therapy is the treatment of choice for cases with neovascular age-related macular degeneration (AMD). Switching to an alternate anti-VEGF has been suggested as a possible option for resistant cases. The purpose of this review is to evaluate whether the timing of switching affects treatment outcomes.

PATIENTS AND METHODS:

A review of published literature was performed looking at all studies where patients with refractory neovascular AMD were switched to an alternative anti-VEGF. Studies were then stratified based on the timing of switching into early (< 12 previous injections) and late (> 12 previous injections).

RESULTS:

A total of 38 studies were identified: 18 where patients were switched early and 20 where they were switched late. Both subgroups showed anatomic improvement after switching, with limited visual gains.

CONCLUSION:

There are insufficient data to recommend early versus late switching. However, both groups showed a reduction of fluid on optical coherence tomography and visual gains in 25% to 30% of patients.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:166–170.]

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in patients older than 50 years in developed countries.1 There are currently three available drugs for the treatment of neovascular AMD: off-label use of bevacizumab (Avastin; Genentech, South San Francisco, CA), on-label use of ranibizumab (Lucentis; Genentech, South San Francisco, CA), and aflibercept (Eylea; Regeneron, Tarrytown, NY). Results from randomized clinical trials (RCTs) have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents in improving vision and preventing visual loss. In the CATT study, patients treated in a fixed monthly dosing regimen with either ranibizumab or bevacizumab gained, on average, 8.2 letters, and patients treated in an as-needed regimen gained 6.4 letters after 1 year of treatment.2 Despite the visual gains achieved, 19% to 22% of patients lost less than four letters, 6.7% of patients lost five to 14 letters, and 5.8% of patients lost more than 15 letters after receiving monthly anti-VEGF therapy.2

However, in clinical practice, many physicians switch anti-VEGF treatments when patients do not show adequate anatomic and/or visual improvements. In fact, a 2016 Preferences and Trends survey for the American Society of Retinal Specialists found that 77% of those surveyed would switch to an alternative anti-VEGF drug in non-responding cases after three to six injections, 12% would switch after fewer than three injections, and 12.5% would switch after more than six injections. Interestingly, although 59% of U.S. retina specialists believed in the efficacy of switching therapies, the remaining 41% were either not sure about this benefit or preferred to not switch drugs.

One of the major issues with regard to switching anti-VEGF drugs is the lack of adequate controlled studies comparing between patients who were treated with a single drug and those treated with different drugs. In addition, there are no studies comparing between switching therapies early in the course of treatment versus switching therapies in a more chronic stage of the disease. The current review looks specifically at the timing of switching in various studies and whether this had an effect on treatment outcomes.

Patients and Methods

The search strategy included searches in Medline, PubMed, and Embase and included the search items “age-related macular degeneration,” “neovascular AMD,” “aflibercept,” “ranibizumab,” “bevacizumab,” “anti-VEGF,” “switch,” “conversion,” “change,” “refractory,” “recalcitrant,” “nonresponders.” and “resistant.” This review only included all published literature prior to August 2016 and studies that switched patients who were refractory to previous anti-VEGF therapy, had a clear definition of refractoriness or nonresponse, had an adequate number of patients (> 10 patients), had an adequate follow-up duration (> 3 months), and were published in English. A total of 38 studies met these criteria.

The exact definition of switching early or late in the course of treatment has not been previously defined for AMD. The post hoc analysis of several RCTs had identified a group of delayed responders (13% to 15%), with a peak response at 12 months after therapy initiation and further stabilization in the following 24 months of the study.3,4 Therefore, for the purpose of this review, early switching was defined as patients who received less than 12 injections in the course of treatment compared to chronic patients who received more than 12 injections. This cut-off point was chosen to separate the effect of a delayed response of treatment in general from the effect of switching to a new anti-VEGF.

Results

Studies on Switching Anti-VEGF Therapies After Less Than 12 Injections

Switching to Ranibizumab: A total of three studies looked at the effects of switching to ranibizumab in nonresponsive cases.

In a retrospective study, Moisseiev et al. looked at 110 patients previously treated with bevacizumab who were switched to ranibizumab.5 Patients were switched early after receiving a mean of 9.2 injections of bevacizumab (47.3% switched after three to six injections). There was no significant improvement in visual acuity (VA) before or after three injections of ranibizumab (VA before switching: 0.50 logMAR, VA after switching: 0.52 logMAR; P = .34). There was a significant decrease in central retinal thickness (CRT) 3 months after switching (CRT before switching: 292 μm, CRT after switching: 255 μm; P = .003). On further analysis, the study found that eyes that either lost greater than 0.1 logMAR (approximately five EDTRS letters) in VA or showed increasing macular thickness in the last three injections immediately prior to being switched were more likely to respond both visually and anatomically to the change of the drug.5 Similar anatomic improvements post-switching were demonstrated by Ehlken et al. and Kucukerdonmez et al.6,7 However, only patients in the study by Ehlken et al. showed visual improvement.6

Switching to bevacizumab: Ehlken et al. and Kucukerdonmez et al. also evaluated the effects of transitioning patients from ranibizumab to bevacizumab. In both studies, none of the patients showed any significant anatomic or visual improvements after switching therapies.6,7 Additionally, Pinheiro-Costa et al., in a retrospective study of 110 eyes, showed that patients previously treated with ranibizumab showed a significant decrease of approximately three letters 12 months after switched to bevacizumab (P < .001).8

In a retrospective study by Waizel et al., 19 patients treated with aflibercept were switched early to bevacizumab after a mean of 6.5 injections.9 Although there was no significant change in vision (P = .84), the CRT improved from 367 μm (SD: 198 μm) to 335 μm (SD: 184 μm) (P = .0065) after a mean of 5.4 bevacizumab injections. These results should, however, be interpreted cautiously because there are no other studies looking at switching from aflibercept to another anti-VEGF.

Switching to aflibercept: A total of nine studies (three prospective and six retrospective studies) evaluated early switching to aflibercept (Table A). In the prospective studies by Kawashima et al., Singh et al., and Massamba et al., patients showed statistically significant decreases in CRT and intraretinal fluid after being switched to aflibercept.10–12 Kawashima et al. showed that 46.7% of patients achieved a dry retina with no signs of fluid activity after switching.10 Singh et al. also demonstrated a statistically significant improvement in visual acuity (+9.2 letters) after 12 months of treatment, with 15% of patients gaining more than 15 letters.11 However, significant visual improvements were not demonstrated by the other two prospective studies.9,12 Furthermore, a decrease in the prevalence of pigment epithelial detachments (PED) by 20% to 30% was also demonstrated by Singh et al. and Massamba et al.11,12

Summary of Studies Looking at Early Switching to Aflibercept (Less Than 1 Year) in Cases Previously Non- or Partially Responsive to Anti-VEGF Therapy Summary of Studies Looking at Early Switching to Aflibercept (Less Than 1 Year) in Cases Previously Non- or Partially Responsive to Anti-VEGF Therapy Summary of Studies Looking at Early Switching to Aflibercept (Less Than 1 Year) in Cases Previously Non- or Partially Responsive to Anti-VEGF Therapy

Table A:

Summary of Studies Looking at Early Switching to Aflibercept (Less Than 1 Year) in Cases Previously Non- or Partially Responsive to Anti-VEGF Therapy

In the retrospective studies by Chatziralli et al., Arcinue et al., Heussen et al., and Griffin et al., no significant improvements in VA after switching to aflibercept were demontrated.13–16 A study by Ricci et al. compared between two switching regimens in cases nonresponsive to ranibizumab: pro re nata (PRN) and fixed bimonthly.17 Although the PRN group did not show any improvements in vision (P = .33), the fixed bimonthly group showed a statistically significant visual improvement of +3 ETDRS letters after 12 months of follow up (P = .008). In addition, only 8% to 25% of patients lost five to 15 letters, with no significant difference between the PRN and fixed regimen groups. The study by Chan et al. also showed a significant improvement in VA of + 4 letters at 6 months after switching (P < .001) but did not find significant differences between patients who were switched from either ranibizumab or bevacizumab to aflibercept.18 Overall, 30% to 40% of patients gained some VA compared to 30% to 55% of patients who showed visual stability without loss of vision. A relatively small percentage of patients (10% to 25%) lost vision after switching.

All the retrospective studies looking at switching from other anti-VEGF therapies to aflibercept showed statistically significant decreases in CRT at the end of follow up.13–18 In the study by Ricci et al., 58% of patients treated with PRN aflibercept and 42% of patients treated in the fixed bimonthly regimen group achieved fluid resolution.17 In the study by Chan et al., all optical coherence tomography parameters (subretinal fluid [SRF] height, PED height, and central macular thickness) significantly improved after switching to aflibercept (P < .001).18 Furthermore, there was no difference in the outcomes of switching to aflibercept regardless of the primary drug (bevacizumab or ranibizumab).

Studies on Switching After More Than 12 Prior Injections

The current review included 20 studies in which patients had received more than 12 previous injections prior to switching (16 retrospective and four prospective) (Table B). These studies included only late switching to aflibercept with no studies being identified where patients were switched late to ranibizumab or bevacizumab.

Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD

Table B:

Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD

Visual Outcomes

From the total of 20 studies, only three reported significant visual improvements: Agdham et al. (+14 letters; P = .001), Chang et al. (+6.9 letters; P < .001), and Kumar et al. (+ 5 letters; P = .004).19–37 In addition, although some studies did not report an overall increase in VA, subgroups of patients demonstrated significant visual gains. Barthelmes et al., in a cohort of 384 patients, showed that although 49% of patients had no change in VA, 10% gained 10 ETDRS letters and 10% lost 10 ETDRS letters.28 Muftuoglu et al, in a retrospective study of 81 eyes, demonstrated that 29% of patients were visually stable, whereas 40% lost five ETDRS letters and 32% gained five ETDRS letters.23 Gharbiya et al., in a retrospective study of 31 eyes, demonstrated that 61% of patients remained stable and 13% of patients lost five ETDRS letters or more.37

A prospective study by Mantel et al. compared patients who, after a mean of 21 injections of ranibizumab with inadequate response, were divided into two groups: a group who continued receiving ranibizumab and a group who was switched to aflibercept.23 This study revealed that there was no significant difference in visual improvements between the two groups (aflibercept group: + two ETDRS letters; ranibizumab group: +0.5 ETDRS letters; P = .07).

Anatomical Outcomes

All studies showed anatomical improvement at the end of follow-up, regardless of the type of fluid: SRF, intraretinal cysts (IRC), or PED. The study by Muftuoglu et al. demonstrated that 58% of eyes with SRF prior to switching achieved visual gains post-switching compared to 42% of eyes with IRC.23 Contrary to these findings, Aghdam et al. demonstrated that the presence of IRC pre-switching was associated with significant anatomic improvement (P = .016), whereas SRF was not associated with an adequate response post-switching (P = .25).31 In addition, most studies demonstrated a significant reduction in PED height and base width, as well as a decrease in the percentage of PED at the end of the study.19,21,28–30 The effect of PED height reduction does not appear to be exclusive to aflibercept, but appears to occur at a much faster rate after switching to aflibercept as demonstrated by Massougnes et al.20

The anatomic improvement occurs regardless the type of anti-VEGF that the patient was receiving prior to switching to aflibercept. In the study by Pinheiro-Costa et al., patients who were previously resistant to treatment with bevacizumab (group 1) or ranibizumab (group 2) were switched to aflibercept and had their outcomes compared. In group 1 there was a decrease of 65.3 μm (P = .051) compared to a decrease of 91 μm in group 2 (P < .001). Switching to aflibercept was also associated with a lower monthly reinjection rate (0.57 after switching vs. 0.76 before switching; P = .001). This study, however, showed no significant visual improvements in either group.25 This is in line with previous data from Chan et al. and Messenger et al.18,33

Reinjection Frequency Post-Switching

With regard to reinjection frequency, several studies showed a reduction in treatment frequency with prolongation of injection intervals.27 The retrospective study by Nagai et al. showed a reduction in average injections by 0.6 in the 6 months post-switch (P < .001).27 Sarao et al. showed that the injection frequency post-switching was significantly reduced by 3.4 injections in the 6 months post-switching compared to the 6 months prior (1.9 vs. 5.3; P < .001) with a 13.6-week reinjection interval.32 Furthermore, Barthelmes et al. demonstrated an increase in the interval between injections from 6 weeks to 8 weeks post-switch, with one less injection per year compared to the pre-switch year.26

Discussion

Based on the review of literature, it is clear that switching, whether early or late, was associated with anatomic improvement, with resolution of both SRF and IRC. There have been two previous review articles that have looked into the effects of switching anti-VEGF drugs in the treatment of AMD.33, 34 None stratified patients based on the timing of switching and included only studies prior to May 2015 (the present study included studies until August 2016).

The anatomic improvement was not accompanied by a statistically significant visual improvement at the end of follow-up in the majority of studies.39 The reason for this discrepancy between VA and anatomy might be explained by the inherent pathology of resistant cases that may be associated with more damage to the photoreceptors. Another possibility is the lack of nonprotocol refractions during the studies' assessments, which negated any visual improvement. However, further scrutiny of the switch studies demonstrated that 20% to 25% of patients switched did have visual improvements, and approximately 40% to 50% showed visual stability. The studies also demonstrated that only a small percentage of patients (10% to 15%) had visual loss (Tables A and B).

One of the challenges of the current review was to define the cut-off point for early versus late switching. The cut-off point of 12 injections might seem controversial, but it was chosen in light of data regarding delayed-responders.2,35 Based on data from previous post hoc analysis and from the current review, it can be suggested that patients who fail to respond may fall into one of three categories: early responders who show an increased resistance to therapy over time (tachyphylaxis), delayed responders, and those who fail to respond at all to therapy from the start (resistance).2,3,35,36 These data also highlight the importance of evaluating switching at different time points to study its effect on each patient category.

There were also some differences seen among the different anti-VEGFs agents. Switching to aflibercept was associated with a reduction in injection frequency with longer injection intervals.26, 32 Switching to ranibizumab showed similar results, but there are much fewer studies available for analysis.4–6 There are no studies looking at the effects of switching to ranibizumab after aflibercept use. Additionally, the current review also found that there are insufficient data to support the strategy of switching to bevacizumab as evidenced by the limited anatomic and visual benefits achieved.5–8

A significant drawback of reviewing data regarding switching anti-VEGF agents is that most of the available studies are retrospective or small prospective reports without control groups. Without adequately designed RCTs comparing the switched patients to a control (unswitched) group, it is difficult to ascertain whether switching itself is effective or whether patients responded because they received standardized timely therapy and/or they are simply delayed responders. More prospective studies comparing outcomes of early and late switching with clear definitions for each time point are required to help guide current treatment practice and determine the efficacy of switching anti-VEGF therapies.

References

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  34. Seguin-Greenstein S, Lightman S, Tomkins-Netzer O. A meta-analysis of studies evaluating visual and anatomical outcomes in patients with treatment resistant neovascular age-related macular degeneration following switching to treatment with aflibercept. J Ophthalmol. 2016;2016:4095852.
  35. Ying GS, Maguire MG, Daniel E, et al. Association of baseline characteristics and early vision response with 2-year vision outcomes in the Comparison of AMD Treatments Trials (CATT). Ophthalmology. 2015;122(12):2523–2531.e1.
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  37. Singh RP, Srivastava S, Ehlers JP, Bedi R, Schachat AP, Kaiser PK. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol. 2014;98Suppl 1:i22–27.

Summary of Studies Looking at Early Switching to Aflibercept (Less Than 1 Year) in Cases Previously Non- or Partially Responsive to Anti-VEGF Therapy

Author Study Design Patients Inclusion Criteria No. of Previous Anti-VEGF Injections Treatment Protocol Injections Received Duration of Follow-Up Mean CRT Change at Final Follow-Up Mean BCVA Change at Final Follow-Up
Kawashima et al.10 Prospective 15 with wet AMD; 26 patients with PCV Wet AMD refractory to RBZ for at least 6 months 8.1 ± 3.1 3 monthly followed by bi-monthly n/a 6 months −70.9±77.4 μm (P = .003); 46.7% dryness in neovascular AMD group; 80.8% dryness in the PCV group AMD group: change from 0.41 logMAR to 0.42 logMAR (P = .699); PCV group: Change from 0.41 logMAR to 0.31 logMAR (P = .003)
Singh et al.11 (ASSESS study) Prospective 26 Active wet AMD with sub-foveal CNV with prior RBZ or BVZ injection at least within 3 months of enrollment 9.62 ± 6.58 3 monthly injections then bimonthly 5 12 months −38.6 μm after 6 months; −50.3 μm after 12 months (P < .001); −20% showed anatomically improved PED +5.9 EDTRS letters (P < .001) after 6 months; +9.2 letters after 12 months (P < .001); 15% gained 15 letters. No patient lost more than 15 letters. 100% of patients visually stable at 6 months.
Massamba et al.12 Prospective 24 Patients previously treated with > 6 injections of RBZ 9.2 3 monthly then PRN N/A 6 months Decrease of CRT from 406 μm to 263 μm, P = .001; PED (decrease from 71% to 42%, P = .016); Decrease in IRC (from 83% to 33%, P = .002), SRF (from 92% to 25%, P = .001); Decrease of ORT from 97% to 75% (P = .219 1.16 logMAR to 1.18 logMAR (no significant difference)
Griffin et al.16 Retrospective 47/47 Minimum of 3 injections of BVZ and/or RBZ (partial responders excluded) 11.3 ± 5.96 3 monthly 3 3 months −75 μm (P < .001) Improvement from 0.56 logMAR to 0.53 logMAR (P = .301)
Heussen et al. 15 Retrospective 71 eyes N/A 9 PRN from start 2.73 4 months Eyes receiving one injection (71): −35.7 μm (P = .021); Eyes receiving two injections (66): −43.3 μm (P = .677); Eyes receiving three injections (45): −90 μm (P = .006) Eyes receiving one injection (71): 0.67 logMAR to 0.65 logMAR (P = .426); Eyes receiving two injections (66): 0.59 logMAR to 0.60 logMAR (P = .677); Eyes receiving three injections (45): 0.56 logMAR to 0.43 logMAR (P = .074)
Arcinue et al.14 Retrospective 63 eyes multiple recurrences or persistence of exudation (poor response to monthly RBZ or BVZ for at least 5 months) Median 13 injections Bimonthly without loading dose; 33.3% were switched back to monthly due persistent fluid after a mean of 37 weeks Seven injections 1 year - Median maximum retinal thickness improved from 355 μm to 248 μm at 1 year(P < .0001)
Ricci et al.17 Retrospective 36 eyes in the PRN switch group, 36 eyes in the fixed dosing regimen group Patients with persistent edema after at least three injections of RBZ Five in the PRN group and 6.5 RBZ injections in the fixed dose group Two groups: PRN and second group with fixed bimonthly after three monthly injections 3.5 in the PRN group; seven in the fixed regimen group; Average injection-free period in the PRN group was 3.5 months 1 year At 12 months: decrease of 94 μm in the PRN group (P = .002); decrease of 148 μm in the fixed regiment group (P < .001); 58% fluid resolution in the PRN group vs 42% in the fixed regimen group At 12 months: 60 letters compared to 63 at baseline (P = .33) in the PRN group; 71 letters compared to 68 letters at baseline (P = .008); Overall 67 letters compared to 65 letters (P = .24); PRN group: 25% lost five to 15 letters, fixed group: 8% lost five to 15 letters. No significant difference between groups. (P = .2)
Chatziralli et al.13 Retrospective 447 eyes At least three previous injections of RBZ within 4 months; Persistent or increasing SRF/IRF or PED on OCT 7 8-weekly with no loading dose 48 weeks Decrease in mean CRT from 271 μm to 239 μm at week 48 (P < .001); 260 μm at baseline to 198 μm at 48 weeks (P < .0001) 0.19 letters at 48 weeks (P = .793); Poor prognostic indicators: increasing age, increasing CRT, the presence of intraretinal fluid, pigment epithelial detachment, and subfoveal thickening; 21% gained >5 letters, 9.6% gained >10 letters, 24.9% lost more than 5 letters, 11.6% of eyes lost >10 letters, 54.1% stable vision
Chan et al.17 Retrospective 189 eyes: 84 with prior RBZ, 95 BVZ, 10 mixed Three prior injections prior to switch with “suboptimal response, persistent or recurrent edema, SRF or PED” 8.6 in the RBZ grp, 4.8 in the BVZ grp and 4.9 in the mixed group Three loading doses then PRN 5.4 injections of AFLB in all groups after switch compared to 6.5 mean number of injections in all groups prior to switch 6 months Decrease in SRF height (−28.6 μm, P < .001); Decrease in PED height (−43.4 μm, P < .001); Decrease in CRT (−24.9 μm, P < .001); No significant difference between RBZ grp, BVZ grp and mixed Improvement of 4 letters after 6 months (P < .001); No significant difference between RBZ grp, BVZ grp, and mixed; PED group achieved less visual gains compared to non-PED group; BCVA improved in 42.3%, unchanged in 42.3% and worse in 15.3%
CATT study43 Patients eligible for switching at 3 months were Prospectively followed for 12 months 126 VA 20/40 or worse; Gain less than one line; Persistent foveal fluid; three injections of RBZ/BVZ 3 PRN injections of the original drug N/A 12 months --53 μm at 1 year (P < .0001); −54 μm (P = .0004) at 2 years; 33% dryness at 1 year; 54% dryness at 2 years +2.8 letters at year 1 (P = .050); +2.9 letters at year 2 (P = .11)
CATT study43 Patients eligible for switching at 6 months were Prospectively followed for 12 months 83 VA 20/40 or worse; Gain less than one line; persistent foveal fluid; six injections of RBZ/BVZ 6 PRN injections of the original drug N/A 12 months −26 μm (P = .04) at year 1; −36 μm (P = .02) at year 2; 32% dryness at year 1; 51% dryness at year 2 +3.3 letters at 1 year (P = .03); 4.9 letters at 2 years (P = .008)

Summary of Studies Looking at Late Switching to Aflibercept in Cases With Neovascular AMD

Author (Year) Eyes/Study Design Inclusion Criteria Mean Previous No. of Injections Aflibercept Regimen Follow-Up Duration Change in VA Change in CRT PED Height Change Visual Gains/Losses Other
Nagai et al. (2016)25 73 eyes, Retrospective Persistent or recurrent edema after 1 year of RBZ/BVZ 31 Treat and extend 6 months Unchanged (p=0.78) Decrease by 19 μm (P < .001) Decrease in cube-root volume after switch was significant (−0.07 mm; P = .007) N/A Reduction in average injections by 0.6 within 6 months (P < .001)
De Massougnes et al. (2016)26 60 eyes, Retrospective Need for monthly re-treatment for at least 9 months prior to switch due to IRC/SRF on OCT; PED > 150 μm in height; No PCV 26.1 RBZ 3 loading doses then PRN 9 months N/A No change in BCVA from 74 EDTRS letters at baseline to 74 letters at month 9 313 μm to 275 μm decrease in height (P = .004) N/A Decrease from 340 μm to 313 μm in the 9 months prior to switch. Rate of decline faster after switch (P = .079)
Barthelmes et al. (2016)27 384 eyes, Retrospective No specific criteria; Original treatment for at least 12 months and switched N/A but mean duration of treatment was 40 months. N/A 12 months 63.4 letters to 63.3 letters at month 12 N/A; Decrease in activity of CNV on OCT from 80% to 58% N/A Unchanged in 49%, 10 or more letter gain in 10% and 10% lost 10 letters Eyes treated for 49 months or more prior to switch had worse vision; Interval increased from 42D to 56D (P < .001); Fewer injections received in year after switch (6.6 vs 7.4, P < .001)
Muftuoglu et al.23 (2016) 81 eyes; Divided into two groups: multiple recurrence and resistant group; Retrospective Patients with 2 or more recurrences after dryness or persistence of fluid after at least 5 months of BVZ/RBZ. 14 8 weekly until fluid resolution then PRN. Median 24.12 months 0.55 logMAR at baseline and 0.56 logMAR at last follow-up. (P > .05 at all points) Maximum retinal thickness decreased at all points (P < .05) (430 μm decrease to 330 μm a 24 months); 50% dryness at 24 months; No difference between groups Decrease of from 120 μm to 70 μm (P < .05); No difference between groups 29% had stable VA, 40% lost one line, 32% gained one line No association with age, percent ELM disruption, percent IS/OS disruption and those who lost vision. SRF associated with visual gain independent of previous recurrences and duration of fluid. Re-injection times 16.86 weeks.
Sarao et al.24 (2016) 92 eyes, Prospective Persistent or recurrent IRC/SRF after at least four injections of RBZ during 6 months 15.2 PRN 12 months +1.8 EDTRS (P>0.05); 22% gained two lines. 66% stabilized. 12% worsened. Decrease of 112 μm (P < .001); Dryness 65% after 12 months N/A 22% gained 2 lines or more, 66% stabilized, 12% worsened Prognostic factors; higher baseline BCVA (P<0.001), baseline CRT. Decrease in number of injections compared to previous 6 months (1.9 vs 5.3, P<0.001), 13.6 weeks mean re-injection time.
Aghdam et al.20 (2016) 22 eyes, Retrospective 3 monthly then PRN 12 months 45.68 letters at baseline to 59.09 letters after 12 months (P = .001) Decrease of CRT from 400 μm to 304 μm (P = .003) N/A Significant reduction of IRC (P = .016), reduction of SRF not significant (P = .25)
Kanesa-thasan et al.19 (2015) 11 eyes, Retrospective n/a 25.7 RBZ/BVZ n/a 18 months n/a n/a PED volume decreased with aflibercept from 0.687 ± 0.837 mm3 to 0.562 ± 0.705 mm3 (P = .02), a decrease of 19% ± 12.27% n/a n/a
Mantel et al.21 (2016) 19 eyes; 10 continued on RBZ (group R) and 11 switched to AFLB (group A); Retrospective Eyes still requiring monthly therapy after 2 years of observe and plan therapy 20 to 21 injections of RBZ Three monthly injections then observe and plan 12 months Mean visual acuity increase by two letters in group A and 0.5 letters in group R (P = .07) Four out of 10 eyes achieved dryness in group A, four out of 11 in group R N/A N/A Retreatment interval was 1.13 months in group A and 1.14 in group R
Major et al.22 (2015) 60 eyes, retrospective Eyes with PED and history of previous > 2 injections of BVZ or RBZ 24.8 N/A (total >6 injections) 12 months logMAR VA remained stable; 0.41 at baseline and 0.42 at 12 months (P = .27) N/A PED height reduced by 53 μm at 12 months (P < .005) N/A N/A
Pinheiro-Costa et al.28 (2015) 85 eyes, |Retrospective Minimum of three injections prior to switch of BVZ (group 1) or RBZ (group 2) N/A N/A 14.7 months Decrease from 58.2 to 55.8 letters in group 1 (p=0.0866). Decrease from 56.4 to 54.5 letters in group 2 (P = .168) Decrease of 65.3 μm in group 1, P = .051 and 91 μm in group 2, P < .001 N/A N/A Lower per month injection rate (0.57 instead of 0.76, P < .001); 90% showed anatomic improvements
Wykoff et al.29 (TURF study- 2014) 46 eyes, Prospective Patients with recalcitrant fluid in patients completing 2 year prospective SAVE trial (2.0 mg ranibizumab) 42 PRN 6 months +0.2 letters (p=0.17) −27.3 μm at month 6. (P = .018); 22% dry at month 6 N/A 9% improved > 5 letters, 9% lost > 5 letters or more N/A
Grewal et al.30 (2014) 21 eyes, Prospective Evidence of persistent exudation (IRC/SRF) on OCT despite > 6 RBZ/BVZ; PCV excluded 29.8 Three monthly followed by bimonthly 12 months 0.42 logMAR at baseline, improved to 0.4 logMAR (p=0.5) CRT decreased from 329 μm to 292 μm (P = .038) PED in 15 eyes decreased from a height of 289 μm to 248.27 μm (P = .002) N/A N/A
Thorell et al.31 (2014) 73 eyes, Retrospective At least 12 months of previous BVZ/RBZ due to persistent or recurrent IRC/SRF 30.7 Treat and extend after dryness 6 months No change in VA (P = .78) Decrease in CRT by 19 μm (P < .001) Decrease in PED cube root volume (−0.07 mm; P = .007) N/A N/A
Gharbiya et al.32 (2014) 31 eyes, Retrospective Persistent IRC/SRF +/− PED with at least six consecutive RBZ prior to AFLB. (PCV excluded) 34.4 Three monthly then PRN 6 months No significant change in BCVA at 6 months (42.5 letters at baseline to 42.8 letters at 6 months, P > .05) Decrease in macular thickness from 449 μm to 269 μm at 6 months (P < .001) Decrease in percentage of PED from 31 to 27 at 6 months. (P > .05); Decrease in height of PED from 262 μm to 183 μm at 6 m. (P < .001) 26% improved visually, 13% lost 5 letters, 61% remained stable. BCVA at 6m strongly correlated with baseline VA and baseline IS/OS layer. Negatively associated with length of prior treatment and SRF.
Messenger et al.33 (2014) 109 eyes, Retrospective Patients received 12 months of prior RBZ/BVZ 21.4 PRN 12 months No effect on visual acuity. No change in VA from 0.51 logMAR at baseline to 0.51 logMAR at year 1. (p=0.89) CRT decreased from 324 μm to 299 μm at 1 year(p=0.0047) N/A 12.8% gained vision and 13.8% lost vision. Aflibercept injection frequency unchanged. No difference between RBZ/BVZ treated eyes in terms of VA/CRT
Hall et al.34 (2014) 30 eyes, Retrospective At least 2 previous injections of anti-VEGF either RBZ/BVZ 14.9 3 monthly the PRN 12 months No change in VA from 0.506 logMAR to 0.521 logMAR (p=0.836) CRT decreased from 261 μm to 237 μm at 12 months (p=0.012) N/A N/A N/A
Bakall et al.35 (2014) 36 eyes, Retrospective Initial response and then recurrent increase or persistent fluid. 25.6 3 monthly then PRN 6 months No significant change in vision (0.45 logMAR to 0.50 logMAR, p=0.36) (approximately 2 EDTRS letters) Decrease in CRT of 65 μm (P<0.05) N/A N/A N/A
Chang et al.39 (2013) 49 eyes, Prospective Prior treatment with at least 4 injections of anti-VEGF in past 6 months and persistent IRC or SRF on OCT. 34.9 3 monthly then bi-monthly 6 months Mean gain of +6.9 letters (P<0.001) Decrease of 89.4 μm (P<0.001) N/A 55% of patients gained more than 5 letters, 2% lost more than 5 letters. 43% stable vision 30% fluid free at 6 months
Kumar et al.36 (2013) 34 eyes, Retrospective Consecutive injections of RBZ for 6 months and persistent subfoveal fluid. 28.6 PRN 6 months Improvement in VA from 0.57 logMAR to 0.47 logMAR (+5 EDTRS letters) (p=0.004). IRC decreased from 65% to 23.5%. SRF decreased from 70% to 18%. PED height decreased from 260 μm to 215 μm (<0.001) N/A N/A
Cho et al.37 (2013) 20 eyes, Retrospective Persistent fluid after RBZ/BVZ 20 PRN 6 months No visual changes (0.54 logMAR to 0.57 logMAR, p=0.49) (approximately 1 EDTRS letter) Decrease from 295 μm to 274 μm (p=0.008) 47% of eyes with PED show decrease in PED height. N/A 89% if eyes showed anatomic improvement after 1 injection. 18% dry after 1 injection
Authors

From the Ophthalmology Department, Alexandria Faculty of Medicine, Alexandria, Egypt (MA); Ophthalmic Research Center and Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (TB); and Cleveland Clinic Cole Eye Institute, Cleveland (TB, FOS, RPS).

Dr. Singh reports grants and personal fees from Regeneron, Genentech, and Novartis; and personal fees from Optos and Zeiss. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Support for this study was provided by an unrestricted grant from Research to Prevent Blindness. The sponsor did not participate in the design, execution, data review, or publishing of this manuscript.

Address correspondence to Rishi P. Singh, MD, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; email: SINGHR@ccf.org.

Received: May 08, 2017
Accepted: August 03, 2017

10.3928/23258160-20180221-03

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