Objective To investigate the effect of aflibercept 2.0 mg in cases resistant to ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment.
Purpose To evaluate the anatomic and visual effect of intravitreal aflibercept 2.0 mg in cases of exudative age-related macular degeneration (AMD) with persistent fluid on optical coherence tomography (OCT) despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment at 1 and 6 months.
Methods Retrospective review at Ophthalmic Consultants of Boston, Boston, Massachusetts, USA of exudative AMD cases with persistent fluid on regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment switched to intravitreal aflibercept 2.0 mg treatment and followed for 6 months. Tabulated data included details of prior treatments, best available visual acuity, central subfoveal thickness on registered spectral domain OCT before and after aflibercept injection centred on the anatomic fovea and macular description before and after aflibercept injection.
Results A total of 353 eyes with exudative AMD were switched to aflibercept during the study period. Of these, 28 eyes in 28 patients had persistent fluid after an average of 20 regular ranibizumab/bevacizumab injections (range 7–37). At 1 month, 89% (25 eyes) showed anatomic improvement and 18% (five eyes) were dry after a single aflibercept injection. Central subfoveal thickness improved from 295 to 272 microns (p<0.001) after one aflibercept injection. After an average of 4.4 aflibercept injections (range 3–6) over 6 months, the central subfoveal thickness remained improved (274 microns, p=0.008); 64% (18 eyes) showed anatomic improvement and a quarter of eyes (25%, seven eyes) were dry. Visual acuity did not improve at 1 month (logarithm of minimum angle of resolution (logMAR) 0.54, Snellen 20/69, p=0.64) or 6 months (logMAR 0.57, Snellen 20/76, p=0.49). Treatment was well tolerated with no adverse events reported.
Conclusions A significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment respond anatomically to aflibercept 2.0 mg. Visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD treated with persistent fluid on ranibizumab and/or bevacizumab.
- Treatment Medical
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The advent of drugs that inhibit vascular endothelial growth factor (VEGF) has revolutionised the treatment of exudative age-related macular degeneration (AMD). Ranibizumab (Lucentis; Genentech/Roche) is a recombinant VEGF-specific antibody fragment whose efficacy and safety have been confirmed in multiple large multicentre trials.1–7 Bevacizumab (Avastin; Genentech/Roche) is a monoclonal VEGF-specific antibody that has been developed for the use of various cancers and has been widely used off-label for the treatment of exudative AMD. In November 2011, aflibercept (Eylea; Regeneron Pharmaceuticals), a recombinant fusion protein that binds to members of the VEGF family, was approved by the US Food and Drug Administration for the treatment of exudative AMD. Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placenta growth factor (PIGF). Its binding affinity for VEGF (Kd=0.5 pM) is substantially greater than that of either bevacizumab (Kd=58 pM) or ranibizumab (Kd=46 pM),8 leading to a potential longer duration of action in the eye and allowing for less frequent dosing, as supported by early clinical trials.9
Studies have shown that persistent fluid is common in cases of exudative AMD treated with anti-VEGF agents. In the Comparison of Age-Related Macular Degeneration Treatment Trials, persistent fluid on optical coherence tomography (OCT) at 1 year ranged from 53.2% among patients who received ranibizumab monthly to 81% among patients who received bevacizumab as needed.10 Clinical trials have not studied the use of aflibercept in patients who have received prior anti-VEGF treatment, with or without persistent fluid. The current study evaluates the visual and anatomic response of intravitreal aflibercept 2.0 mg in exudative AMD cases with persistent subretinal or intraretinal fluid on regular ranibizumab and/or bevacizumab treatment.
Patients and methods
Institutional review board exemption was granted from Chesapeake Research Review, Inc., Columbia, Maryland, USA. Medical records of exudative AMD patients treated with intravitreal aflibercept 2.0 mg between 19 November 2011 and 26 June 2012 at Ophthalmic Consultants of Boston, Boston, Massachusetts, USA were retrospectively reviewed. All consecutive eyes exhibiting persistent intraretinal or subretinal fluid on spectral-domain, volume scan OCT despite regular treatment with ranibizumab and/or bevacizumab were included. Eyes were included if: (1) they had persistent intraretinal or subretinal fluid 28–35 days after a minimum of six ranibizumab and/or bevacizumab injections prior to switching to aflibercept; (2) they had their last injection of ranibizumab and/or bevacizumab within 28–35 days of switching to aflibercept; (3) they had a follow-up OCT and examination 28–35 days after switching to aflibercept. Eyes were excluded if: (1) they received ranibizumab or bevacizumab less than 28 days or longer than 35 days prior to switching to aflibercept; (2) the OCT was dry at any time during the 3 months before switching to aflibercept (allowing inclusion of previously responsive or tachyphylactic eyes); (3) the OCT and/or fluorescein angiography suggested outer retinal tubulation without intraretinal or subretinal fluid, pigment epithelial detachment without intraretinal or subretinal fluid, or cystic degeneration, which often overlies areas of retinal pigment epithelium atrophy but does not leak on angiography; (4) they did not have 6 months of follow-up on aflibercept injections.
Tabulated data included patient age, details of prior treatments (ie, bevacizumab, ranibizumab), non-best corrected but best available visual acuity (eg, spectacle-corrected and pinhole), central subfoveal thickness on registered spectral domain OCT (SD-OCT) before and after aflibercept injection centred on the anatomic fovea, and macular description before and after aflibercept injection. This study allowed inclusion of pigment epithelial detachments as long as there was associated subretinal and/or intraretinal fluid. Because this was a retrospective study, best-corrected visual acuity, or carefully refracted Early Treatment Diabetic Retinopathy Study visual acuity, was not available. Visual acuities were converted to logarithm of minimum angle of resolution (logMAR) for statistical analysis.11 Counting fingers vision was converted to logMAR=2, and hand motions was converted to logMAR=3. SD-OCT images were obtained using the Heidelberg Spectralis (Heidelberg Engineering Inc., Vista, California, USA) and the Zeiss Cirrus-HD OCT software V.4.5 (Cirrus HD-OCT; Carl Zeiss Meditec) depending on which office the patients were seen. OCT images were obtained using the same machine for all pre-aflibercept and post-aflibercept visits to allow for registration and direct comparison of scans. Central subfoveal thickness was measured using the automated software. Manual registration of pre- aflibercept and post-aflibercept OCT images was done in cases of inaccurate automated registry. Two-tailed student's paired t-tests were performed to analyse visual and anatomic outcomes (Microsoft Excel, Redmond, Washington, USA).
A total of 353 eyes with exudative AMD were switched to aflibercept 2.0 mg during the study period. Of these, 28 eyes in 28 patients met inclusion/exclusion criteria with persistent subretinal or intraretinal fluid on ranibizumab/bevacizumab treatment (table 1). Almost all eyes had classic or occult choroidal neovascularisation, though one eye had retinal angiomatous proliferation. The mean age at time of aflibercept switch was 81 years (range 62–95). An average of 20 prior ranibizumab/bevacizumab injections (range 7–37) were given. After switching to aflibercept, patients were re-evaluated at a mean of 32 days (range 28–35). Patients were treated monthly, but 21 (75%) were extended to 6–8 weeks within the 6-month study period.
At 1 month, 89% (25 eyes) showed anatomic improvement after a single intravitreal aflibercept 2.0 mg injection. The majority of eyes with recalcitrant subretinal fluid improved (86%, 19 of 22 eyes). Of those with persistent intraretinal fluid, 86% showed improvement (7 of 8 eyes). Half showed improved sub-RPE fluid with smaller pigment epithelial detachments (50%, 6 of 12 eyes). Eighteen percent (5 of 28 eyes) were completely dry after a single aflibercept injection.
The 6 month visit occurred at an average of 171 days (range 134–192 days). Eyes received an average of 4.4 aflibercept injections (range 3–6). At 6 months, 64% (18 of 28 eyes) showed anatomic improvement. The majority of eyes with persistent subretinal fluid had some degree of improvement (64%, 14 of 22 eyes), while nearly a quarter were stable (23%, 5 of 22 eyes), and 14% (3 of 22 eyes) worsened at 6 months. Of those with persistent intraretinal fluid, 63% showed improvement (5 of 8 eyes), 25% (2 of 8 eyes) were stable and 13% (1 of 8 eyes) worsened at 6 months. Nearly half of eyes with pigment epithelial detachments had some improvement in the height (47%, 7 of 15 eyes) at 6 months; 53% (8 of 15 eyes) were stable and none got worse. A quarter of eyes (25%, 7 of 28 eyes) were completely dry at the 6-month follow-up visit (figure 1).
Central subfoveal thickness improved from 295 to 272 microns on registered SD-OCT (p=0.0001) at 1 month, and remained improved at 6 months (274 microns, p=0.008). Visual acuity did not improve at 1 month (logMAR 0.52–0.54, Snellen 20/67–20/69, p=0.64) or 6 months (logMAR 0.57, Snellen 20/76, p=0.49) (table 2); there was a non-significant trend towards decreased visual acuity.
No eyes developed significant ocular safety events such as endophthalmitis, non-infectious endophthalmitis, vitreous haemorrhage, retinal tear, retinal detachment or sustained elevations in pressure.
The treatment of exudative AMD continues to evolve. Numerous groups have observed anatomic and sometimes visual improvement after switching to aflibercept in cases with persistent fluid on prior anti-VEGF treatment, reporting similar findings to the current study12–18; as of this writing, no studies have been published.
In the present study, there was significant anatomic improvement after a single aflibercept injection with gains maintained at 6-month follow-up. There are several possible explanations for the observed anatomic benefit after switching to aflibercept, including its pharmacodynamics and the possibility of tachyphylaxis to prior treatment with ranibizumab/bevacizumab. As mentioned, aflibercept binds all isoforms of VEGF-A and VEGF-B, as well as PIGF, with a significantly higher binding affinity for VEGF than either ranibizumab or bevacizumab. Mathematical models predict that a single intravitreal injection of aflibercept 2.0 mg would last between 48 and 83 days (compared with 30 days for ranibizumab) and thus should be efficacious in neutralising VEGF longer and more effectively.10 Both VEGF-B and PIGF have been implicated in the neovascularisation process of AMD. It is possible that eyes included in this study were not at the peak of their dose-response curve while on prior treatment. However, the HARBOR study failed to find an anatomic or visual difference between 0.5 mg and 2.0 mg of ranibizumab for exudative AMD at 3 years, suggesting that in their overall study population ranibizumab 0.5 mg was sufficient.19 It is possible that greater VEGF blockage might be helpful for a recalcitrant subset of exudative AMD eyes, as supported by the SAVE trial.20
Tachyphylaxis, or a decreasing therapeutic response to a pharmacologic agent following repeated administration over time,21 is another possible explanation for the observed effect after switching to aflibercept. Eyes with choroidal neovascularisation experiencing an initial morphological response to ranibizumab or bevacizumab therapy but later developing tachyphylaxis despite repeated injections can show an improved response when switched to a different anti-VEGF drug.22–24 The anatomic gains in this study were maintained through 6 months on aflibercept. Most likely, both the pharmacodynamics and the possibility of tachyphylaxis are playing roles in aflibercept's observed improvement of previously persistent fluid.
It is unclear if a drier macula achieves better long-term visual acuity. The present study did not find any visual gain (non-best corrected) at 1 or 6 months after switching to aflibercept, and there was a non-significant trend towards worsening visual acuity. In our cohort of patients with persistent fluid despite an average of 20 prior injections of ranibizumab and/or bevacizumab, chronic photoreceptor degeneration might have limited the visual potential after switching to aflibercept. Smaller studies reported significant visual gains after switching to aflibercept,13 ,17 while others have shown no improvement.14 ,15 ,18 In VIEW one and two, survival analysis found eyes treated with aflibercept had resolution of macular fluid sooner than eyes treated with ranibizumab, yet there was no clear visual advantage at 1 year.25 ,26 In the combined VIEW trials, 38% of eyes in the ranibizumab arm had persistent fluid at 1 year, compared with 27.6% in the aflibercept 2 mg every 4-week arm, and 32.3% in the aflibercept 2 mg every 8-week arm.27 ,28 It is possible that in a subset of eyes with persistent fluid due to exudative AMD, despite regular ranibizumab and/or bevacizumab treatment, the observed anatomic benefit of aflibercept might make a long-term visual difference.
The strength of the present study is the homogeneity of included eyes with strict inclusion and exclusion criteria, and 6 months of follow-up with a recently approved medication. Limitations of our study include the small cohort, its uncontrolled retrospective design, non-best corrected (but best available) visual acuity, and non-standard treatment protocols. Further, fluorescein angiography was not always performed prior to switching to aflibercept, and the determination of persistent fluid was made on spectral domain, volume scan OCT alone. Future prospective studies could evaluate various protocols switching eyes to aflibercept and evaluate efficacy and costs of individualised treatments for eyes with and without persistent fluid on ranibizumab and/or bevacizumab.
In summary, a significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab and/or bevacizumab treatment respond anatomically to aflibercept 2.0 mg at 1 month, with gains maintained at 6 months. Non-best corrected visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD with persistent fluid on ranibizumab and/or bevacizumab.
Summary Statement: Aflibercept 2.0 mg may be beneficial in exudative age-related macular degeneration (AMD) cases with persistent fluid on ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment.
Collaborators Tina S Cleary MD, Torsten W Wiegand MD PhD, Michael G Morley MD, Trexler M Topping MD.
Contributors All authors listed have made substantive intellectual contributions to this study including the conception and design, acquisition of data, analysis/interpretation of data, revisions and final approval of the version to be published.
Competing interests HC, MWnone; CPS—Sub-investigator on studies with the following sponsors: Alcon, Alimera, Allergan, Fovea, Genentech, Genzyme, Partners, Neovista, Novartis, Ophthotech, Regeneron; JSH—Consultancy: Acucela, Aerpio, Allergan, Bausch & Lomb, Bayer, Endo Optiks, Fovea, Genentech, Genzyme, GlaxoSmithKline, Kanghong, Notal Vision, Oraya, Paloma, QLT, Regeneron, Sequenom; Research Grant: Alcon, Alimera, Allergan, Fovea, Genentech, Genzyme, GlaxoSmithKline, Neovista, Notal Vision, Novartis, Ophthotech, Paloma, Regeneron.
Ethics approval Chesapeake Research Review, Inc., Columbia, MD.
Provenance and peer review Not commissioned; externally peer reviewed.
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