Intravitreal Aﬂibercept for TreatmentResistant Neovascular Age-related Macular Degeneration Andrew A. Chang, FRANZCO, PhD,1,2 Haitao Li, MBBS, PhD,1 Geoffrey K. Broadhead, MBBS,1,2 Thomas Hong, MScMed, BAppSc,1 Timothy E. Schlub, BSc(Hons), PhD,3 Wijeyanthy Wijeyakumar, MOTH, BSc,1,2 Meidong Zhu, MBBS, PhD2 Objective: To assess the effectiveness of intravitreal aﬂibercept in patients with neovascular age-related macular degeneration (AMD) previously resistant to treatment with other antievascular endothelial growth factor agents. Design: Prospective, open-label, noncontrolled, registered clinical trial. Participants: Forty-nine patients with treatment-resistant neovascular AMD. Intervention: A dose of 2 mg intravitreal aﬂibercept was administered as 3 initial loading doses every 4 weeks (week 0, week 4, and week 8), followed by further injections every 8 weeks (weeks 16 and 24) across a 24week period in total. All patients underwent a complete ophthalmic examination, including measurement of Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), intraocular pressure assessment, adverse event monitoring, and spectral-domain optical coherence tomography at every visit. Baseline ﬂuorescein angiography and indocyanine green angiography also were performed. Main Outcome Measures: Outcomes assessed included proportions of patients with a gain or loss of more than 5 ETDRS letters and a decrease or increase in central retinal thickness (CRT) of more than 150 mm at week 24 compared with baseline, change in mean BCVA and CRT between baseline and week 24, and descriptive safety data. Results: The BCVA improved and CRT was reduced signiﬁcantly at all follow-up visits compared with baseline (P < 0.001), with a mean improvement of 6.9 letters of BCVA and a decrease of 89.4 mm in CRT at week 24. Spacing of injections from every 4 weeks to 8 weeks resulted in an increase of 37.4 mm in CRT (P < 0.001); however, this was not correlated with a signiﬁcant change in vision. There was 1 (2%) patient who lost more than 5 ETDRS letters, and 27 (55%) patients who gained more than 5 letters. Two (4%) patients had a more than 150 mm increase in CRT at week 24, and 10 (20%) patients showed a decrease in CRT of more than 150 mm. Conclusions: Intravitreal aﬂibercept is effective in previously treatment-resistant neovascular AMD. Further follow-up is required to determine whether these improvements can be maintained. Ophthalmology 2014;121:188192 ª 2014 by the American Academy of Ophthalmology.
Neovascular age-related macular degeneration (AMD) is a leading cause of visual loss in aging populations.1,2 Current standard therapy involves the intravitreal administration of monoclonal antibody-based therapies directed against vascular endothelial growth factor (VEGF). The 2 most widely used agents are ranibizumab (Lucentis; Genetech, Inc, South San Francisco, CA) and bevacizumab (Avastin; Genetech, Inc).3 The Comparison of Age-Related Macular Degeneration Treatments Trials showed that, with monthly ranibizumab therapy, optical coherence tomographydetectable macular ﬂuid was present in 53.2% and 51.5% of patients after 1 and 2 years of therapy, respectively.4,5 Less frequent injections or bevacizumab use resulted in even greater percentages of patients with persistent retinal ﬂuid.5 This persistent macular ﬂuid may result in ongoing visual impairment. Aﬂibercept (VEGF-Trap Eye/Eylea; Regeneron, Tarrytown, NY) is a recently approved anti-VEGF agent with
2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
greater binding activity to VEGF molecules than either ranibizumab or bevacizumab.6,7 The VEGF-Trap Eye: Investigation of Efﬁcacy and Safety in Wet AMD (VIEW) 1 and VIEW 2 studies demonstrated that aﬂibercept given every 2 months after 3 initial loading doses was noninferior to monthly ranibizumab in maintaining vision in patients with treatment-naïve neovascular AMD over a 1-year period.8 Given the efﬁcacy of aﬂibercept in treatment-naïve eyes, it is conceivable that improved anatomic and functional outcomes also may be achievable in patients with previously treatment-resistant choroidal neovascularization (CNV). Several retrospective studies have showed that individualized aﬂibercept treatment can reduce retinal ﬂuid effectively and can preserve vision in treatment-resistant AMD patients.9e12 However, the efﬁcacy of the recommended aﬂibercept treatment regimen (every 2 months after 3 initial loading doses) in managing treatment-resistant AMD ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.08.035
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patients has not yet been reported. The purpose of this study was to evaluate prospectively the effectiveness of intravitreal aﬂibercept in patients with treatment-resistant AMD.
Methods Study Design A prospective, open-label clinical trial was conducted on 50 patients attending a tertiary retinal clinic between August and October 2012. All patients were followed up for 24 weeks. Institutional ethics approval was obtained before study commencement, and the trial was listed on the Australian and New Zealand Clinical Trials Registry (accessible via www.anzctr.org.au, registered on June 21, 2012; ACTRN no. 12612000666820). This study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants before enrollment in the study.
Population Inclusion criteria refer to the study eye only and were as follows: known CNV secondary to AMD as demonstrated by ﬂuorescein angiography; prior treatment with at least 4 injections of antiVEGF agents in the past 6 months and persistent intraretinal or subretinal ﬂuid, or both, on spectral-domain optical coherence tomography during this period; and best-corrected visual acuity (BCVA) between 35 and 90 Early Treatment Diabetic Retinopathy Study (ETDRS) chart letters (equivalent to 6/60e6/6 Snellen acuity). The above criteria were considered consistent with treatment resistance to previous anti-VEGF agents. Exclusion criteria were: uncontrolled intraocular pressure (IOP) of more than 25 mmHg; current vitreous hemorrhage or inﬂammation; prior vitrectomy or AMD-related surgery or any intraocular surgery within 2 months of study commencement; anti-VEGF therapy within the previous 30 days; photodynamic therapy within the previous 90 days or more than 6 prior photodynamic therapy treatments; treatment with intravitreal triamcinolone within the previous 180 days; presence of signiﬁcant subretinal ﬁbrosis or atrophy; signiﬁcant corneal or lenticular opacities; myocardial infarction, transient ischemic attack, or cerebrovascular accident within the previous 90 days; and current pregnancy or lactation. All ocular exclusion criteria refer to the study eye only.
Study Protocol Three initial loading doses of intravitreal aﬂibercept (2 mg) were administered at 4-week intervals (week 0, week 4, and week 8), followed by further injections of aﬂibercept at weeks 16 and 24. Patients were reviewed 1 week after the initial injection, then monthly regardless of injection status. At each visit, a full ophthalmic examination, including BCVA and IOP assessment with Goldman applanation tonometry, adverse event monitoring, fundus photography (ﬂuorescein angiography), and spectral-domain optical coherence tomography (Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany) measurement of both eyes were conducted. Nuclear, cortical, and posterior subcapsular lens opacities were graded according to the Age-Related Eye Diseases Study grading protocol in all phakic eyes.13 Fundus ﬂuorescein angiography and indocyanine green angiography were performed at the baseline visit to conﬁrm the presence of AMD-related CNV and to exclude potential masquerade lesions such as polypoidal vasculopathy. Central retinal thickness (CRT) was calculated from a 19-line Heidelberg Spectralis scan with 1028 A-scans per line. Inbuilt Heidelberg licensed software with eye tracking and image recognition (Tru-Track and AutoRescan, respectively) was used to ensure continuity of the scan location throughout the follow-up
period. Central retinal thickness was deﬁned as the distance between the internal limiting membrane and Bruch’s membrane. The anatomic boundaries on all B-scans were reviewed by at least 2 imaging graders (W.W., G.B., H.L., T.H.) to ensure that the automated segmentation algorithms accurately identiﬁed the internal limiting membrane and Bruch’s membrane layers. Where necessary, the segmentation lines and central foveal location were manually redeﬁned.
Injection Procedure All injections were performed according to a standardized procedure in an operating room setting by a single surgeon (A.C.). Patients were prepared via administration of topical anesthesia (benoxinate hydrochloride 0.4%), followed by application of a topical antimicrobial (Povidine iodine 5% [Sanoﬁ, Paris, France] or chlorhexidine 0.1% [Pﬁzer, New York, NY] in the case of documented prior iodine allergy). The injection was performed using a 30-gauge needle through the pars plana. Patients were prescribed topical chloramphenicol solution 0.5% 4 times daily for 1 week after injection.
Statistical Analysis Visual statistical analyses included mean change in BCVA, percentage of patients with a gain or loss of more than 5 ETDRS letters at week 24 compared with baseline, and the mean change in BCVA when injection frequency was spaced from every 4 weeks to every 8 weeks. Anatomic statistical analyses included mean change in CRT at week 24 compared with baseline, percentage of patients with a decrease or increase in CRT of 150 mm or more compared with baseline, ﬂuid-free status, and the change in CRT when injection frequency was increased from every 4 weeks to every 8 weeks. Visual and anatomic thresholds were designed to assess equivalence of aﬂibercept therapy with previous anti-VEGF agents. The frequency of ocular and systemic adverse events, including endophthalmitis, retinal detachment, elevated intraocular pressure requiring topical ocular hypertensive medications, uveitis, and thromboembolic events were recorded. An increase in lens opacity grading of 2 or more Age-Related Eye Diseases Study levels in either nuclear, cortical, or posterior subcapsular cataract, IOP of 25 mmHg or more or a rise in IOP of 10 mmHg or more compared with baseline were considered to be an adverse event. Statistical analyses were performed using R version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria). Paired t tests were used to compare the differences in means between baseline and follow-up examinations for BCVA and CRT. A P value of less than 0.05 was considered to be statistically signiﬁcant. In instances where patients did not attend a scheduled visit, the last observation was carried forward for analysis.
Results Patient Baseline Characteristics Fifty patients initially were enrolled in the study, and 1 patient was excluded from analysis because of prior vitrectomy surgery in the study eye. Baseline characteristics of the 49 participants are presented in Table 1. The mean age at baseline was 77.87.5 years and 28 patients (57%) were female. Baseline mean standard deviation BCVA was 60.516.2 letters, and baseline CRT was 448.4141.2 mm. Thirty-two (65%) of 49 eyes were phakic at baseline, and 31 (97%) of these had presence of either nuclear, cortical, or posterior subcapsular lens opacities. All 49 patients had received at least 4 ranibizumab injections within the 6 months before switching to aﬂibercept. Among them,
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Table 1. Baseline Characteristics of Patient Cohort Characteristic
No. of participants Age (yrs), mean SD Male (%) Right eyes, n (%) Phakic and pseudophakic eyes (%) Nonsmokers (%) Former smokers (%) Current smokers (%) Ranibizumab treatment period (yrs), mean SD Total no. of ranibizumab injections, mean SD No. of ranibizumab injections 6 months before study, mean SD Ranibizumab injections, no. (%) Ranibizumab and bevacizumab 6 mos Ranibizumab and Bevacizumab >6 mos and PDT >6 mos
49 77.87.5 42.9 23 (46.9) 65.3, 34.7 38.8 57.1 4.1 3.41.7 34.916.1 5.00.7 49 7 (14.3) 1 (2.0) 1 (2.0)
PDT ¼ photodynamic therapy; SD ¼ standard deviation.
40 (82%) of 49 patients had ranibizumab monotherapy and 7 (14%) of 49 patients received at least 4 ranibizumab injections plus at least 1 bevacizumab injection within the 6 months before the commencement of the aﬂibercept study. One patient had received photodynamic therapy and bevacizumab more than 6 months before switching, and 1 patient had received bevacizumab more than 6 months before baseline aﬂibercept treatment.
Visual Changes Best-corrected visual acuity improved signiﬁcantly at all follow-up visits compared with baseline (P < 0.001), with a gain of 6.98.12 letters at week 24 (Fig 1). At week 24 after aﬂibercept treatment, 55% of eyes improved by 5 letters or more, 26% improved by 10 letters or more, and 10% improved by 15 letters or more. Forty-three percent of eyes were stable (5 ETDRS letters compared with the baseline value). Only 1 patient (2%) lost more than 5 ETDRS letters. Spacing of therapy from every 4 weeks to every 8 weeks did not result in a signiﬁcant reduction of BCVA (P > 0.05). This was assessed by comparing the mean BCVA at both week 16 and week 24 (8 weeks since previous injection) with the mean BCVA at week 12 and week 20 (both 4 weeks after injection). The mean BCVA change from week 12 to week 16 (1.14.6 letters) and from week 20 to week 24 (1.05.1 letters) was not signiﬁcantly different (P > 0.05 for both).
Figure 1. Graph showing the change in mean best-corrected visual acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS] letters) over 24 weeks compared with baseline values. Error bars represent standard deviation.
week 24 (8 weeks since previous injection), the mean CRT was signiﬁcantly greater than at the preceding month (mean CRT change from week 12 to week 16 was 37.4 mm and mean CRT change from week 20 to week 24 was 42.9 mm; P < 0.001 for both).
Adverse Events There were 4 serious ocular adverse events (Table 2). An extensive submacular hemorrhage developed at week 22 in 1 patient that resulted in an 18-letter decrease in BCVA. This is the only patient with BCVA decrease of more than 5 letters in the study. Another patient had a pre-existing subretinal hemorrhage at baseline that worsened at week 4 after the initial injection. The hemorrhage gradually resolved during the next 20-week period. One patient had an increase in Age-Related Eye Diseases Study cortical cataract grade of 2 levels. Pseudophakic cystoid macular edema (Irvine-Gass syndrome) developed in a single patient after cataract extraction and intraocular lens implantation in the nonstudy eye. There were no other signiﬁcant ocular adverse events observed, including elevated IOP, retinal detachment, or endophthalmitis. A single systemic arterial thromboembolic event occurred at the month 6 visit. The patient sustained an acute myocardial infarction requiring hospitalization and placement of 3 drug-eluting coronary artery stents. Other systemic adverse events are listed in Table 2.
Anatomic Changes Central retinal thickness reduction was signiﬁcant for all follow-up visits compared with baseline (P < 0.001 for all; Fig 2). The maximum reduction in CRT occurred at 12 and 20 weeks, which was 4 weeks after injection, with a maximum mean reduction of 127134 mm at week 12 and 132130 mm at week 20. At the last measurement time for this study (week 24), 33% of eyes had a more than 100-mm CRT reduction, and in 10 (20%) patients, CRT decreased by more than 150 mm. There were 63% of eyes with stable CRT (100 mm compared with the baseline value). Two (4%) patients showed an increase in CRT of more than 150 mm at week 24. Twenty-two (45%) of 49 patients were ﬂuid free at week 12, and 10 (20%), 20 (41%), and 14 (29%) patients were ﬂuid free at week 16, week 20, and week 24, respectively. Spacing of therapy from every 4 weeks to every 8 weeks resulted in a statistically signiﬁcant increase in CRT. At both week 16 and
Figure 2. Graph showing the change in mean central retinal thickness (in micrometers) over 24 weeks compared with baseline values. Error bars represent standard deviation.
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Table 2. Ocular and Systemic Adverse Events Event
Pseudophakic cystoid macular edema (nonstudy eye) Submacular hemorrhage Cortical cataract Pneumonia Atrial ﬁbrillation Gastritis Spondylolisthesis (requiring operative management) Syncope Deep vein thrombosis Myocardial infarction
1 2 1 1 2 1 1 1 1 1
Discussion Aﬂibercept has been shown to be effective in treating neovascular AMD in treatment-naïve patients. The present study provides evidence that intravitreal aﬂibercept improved visual and anatomic outcomes in patients with neovascular AMD who were resistant to previous antiVEGF therapy. The improvement in vision and macular structure was evident after 3 loading injections at monthly intervals. Vision remained stable when injections were spaced to every 8 weeks despite the oscillating pattern of CRT. Our ﬁndings are similar to those of a study by Kumar et al,9 who also found a visual improvement of approximately 1 line (Snellen equivalent) over a 6-month study period. This contrasts with other recent retrospective studies that found no signiﬁcant improvement in vision in a similarly treatment-resistant population.10e12,14 Possible explanations for the discrepancies in results among the studies include shorter follow-up durations, nonstandardized measurement and therapy protocols, and differing treatment washout periods. Additionally, the absence of angiographic assessment at baseline may not have detected and excluded masquerade lesions such as polypoidal vasculopathy that potentially may have confounded these results. There was an increase in mean CRT when injection frequency was spaced from 4 to 8 weeks. Our results were consistent with the oscillating pattern of CRT change seen in the VIEW studies.8 The ﬂuctuating pattern of CRT when injections were spaced to every 8 weeks suggests that the effects of aﬂibercept may not last for this duration. However, this pattern does not seem to impact signiﬁcantly on vision. The CRT change was reversible with reinjection of aﬂibercept. It is currently not known whether ﬂuctuating subretinal or intraretinal ﬂuid, or both, is associated with long-term visual impairment, and further research is required to clarify this issue. Subretinal hemorrhage developed in 1 patient, and 1 patient experienced worsening of an existing subretinal hemorrhage that subsequently resolved during the study period. It is uncertain if these adverse events were related directly to any effect of aﬂibercept on retinal vasculature. The single patient in whom a signiﬁcant cortical cataract developed still achieved an improved BCVA at week 24 compared with baseline.
One patient with signiﬁcant vascular risk factors including hypertension and hypercholesterolemia experienced a myocardial infarction after his fourth aﬂibercept injection. Previously, the VIEW studies did not demonstrate an increased risk of myocardial infarction with aﬂibercept therapy as compared with ranibizumab.7 Further research is needed to investigate the systemic effects of long-term intravitreal aﬂibercept therapy. The strengths of this study include its prospective design; rigorous previous treatment with anti-VEGF therapies for all patients; and standardized inclusion and exclusion criteria, examinations, treatment procedures, and grading methods. Baseline investigations, including angiography, excluded potential confounding lesions such as polypoidal vasculopathy. There are some limitations of this study, including the relatively small sample size and the lack of a control group. Further follow-up is required to determine the longterm efﬁcacy of aﬂibercept treatment in these treatmentresistant neovascular lesions. This study provides evidence that aﬂibercept can improve visual and anatomic outcomes successfully in patients who are resistant to previous anti-VEGF therapy. These beneﬁts can be maintained effectively after spacing treatment intervals to 8 weeks. Reduced injection frequency lessens the risk of drug- and procedure-related complications. Aﬂibercept therapy in this difﬁcult-to-manage patient subgroup achieves improved vision and CRT with less frequent injections, thereby reducing the burden monthly treatment places on both patients and their treating physicians. Longer-term follow-up is required to assess the efﬁcacy of aﬂibercept further in this setting.
References 1. Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122:477–85. 2. Klaver CC, Wolfs RC, Vingerling JR, et al. Age-speciﬁc prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol 1998;116:653–8. 3. Curtis LH, Hammill BG, Qualls LG, et al. Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 Medicare beneﬁciaries. Am J Ophthalmol 2012;153: 1116–24. 4. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–908. 5. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119:1388–98. 6. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667–8. 7. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171–85. 8. Heier JS, Brown DM, Chong V, et al. VIEW 1 and VIEW 2 Study Groups. Intravitreal aﬂibercept (VEGF Trap-Eye) in wet
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age-related macular degeneration. Ophthalmology 2012;119: 2537–48. 9. Kumar N, Marsiglia M, Mrejen S, et al. Visual and anatomical outcomes of intravitreal aﬂibercept in eyes with persistent subfoveal ﬂuid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 2013;33:1605–12. 10. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aﬂibercept for chronic refractory or recurrent neovascular agerelated macular degeneration. Am J Ophthalmol 2013;156: 29–35. 11. Bakall B, Folk JC, Boldt HC, et al. Aﬂibercept therapy for exudative age-related macular degeneration resistant to
bevacizumab and ranibizumab. Am J Ophthalmol 2013;156: 15–22. 12. Ho VY, Yeh S, Olsen TW, et al. Short-term outcomes of aﬂibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors. Am J Ophthalmol 2013;156:23–8. 13. Age-Related Eye Disease Study Research Group. The AgeRelated Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report no. 4. Am J Ophthalmol 2001;131:167–75. 14. Schachat AP. Switching anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Am J Ophthalmol 2013;156:1–2.
Footnotes and Financial Disclosures Originally received: June 14, 2013. Final revision: August 7, 2013. Accepted: August 27, 2013. Available online: October 18, 2013. 1
Financial Disclosure(s): The author(s) have made the following disclosure(s): Andrew A. Chang: ConsultantdAlcon, Bayer, Novartis. Manuscript no. 2013-950.
Sydney Institute of Vision Science, Sydney, Australia.
Save Sight Institute, The University of Sydney, Sydney, Australia. Sydney School of Public Health, The University of Sydney, Sydney, Australia.
Presented at: International Symposium on Ocular Pharmacology and Therapeutics, March 2013, Paris, France; and Association for Research in Vision and Ophthalmology Annual Meeting, May 2013, Seattle, Washington.
Supported by Bayer Corporation Global (Bayer Healthcare AG, Leverkusen, Germany). The sponsor had no role in the design or conduct of this research. Correspondence: Andrew A. Chang, MBBS, PhD, Sydney Retina Clinic & Day Surgery, Level 13, Park House, 187 Macquarie Street, Sydney, NSW, 2000, Australia. E-mail: [email protected]