REFRACTORY INTRARETINAL OR SUBRETINAL FLUID IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL RANIZUBIMAB Functional and Structural Outcome CHRISTINA GIANNIOU, MD,*† ALI DIRANI, MD,*† LIUNA JANG, MD,*† IRMELA MANTEL, MD*† Purpose: To investigate the visual acuity results of eyes with neovascular age-related macular degeneration and refractory fluid despite monthly treatment with ranibizumab, and to investigate differences between refractory subretinal fluid and intraretinal cystic changes. Methods: Retrospective chart review of consecutive treatment-refractory neovascular age-related macular degeneration, defined as persistent intraretinal or subretinal fluid despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, type and location of the refractory fluid, mean visual acuity change, number of injections, and the time point of first complete disappearance of all fluid on spectral domain optical coherence tomography. Results: Seventy-six eyes (74 patients, mean age, 76.8 years) were identified. The mean follow-up was 33.6 months (range, 12–73 months). The mean number of injections was 11.4 in the first year and 27.7 over follow-up. The refractory fluid was located subfoveally in 61.8%. In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13–49 months). Mean visual acuity increased by 9.0, 7.9, and 7.9 letters by Month 12, Month 24, and Month 36, respectively. Subgroup analysis revealed a higher risk for fibrosis (odds ratio, 3.30) or atrophy (odds ratio, 3.34) in patients with refractory cysts as compared with refractory subretinal fluid. Furthermore, refractory cysts showed a higher risk for a 10-letter visual acuity loss (P = 0.018). Conclusion: Fluid refractory to monthly treatment with ranibizumab for neovascular agerelated macular degeneration still allowed for well-maintained visual improvement, even in subfoveal location. Late fluid resolution may occur. However, refractory cysts were associated with poorer anatomical and functional outcome than subretinal fluid. RETINA 35:1195–1201, 2015
N
opment of a fibrovascular scar and/or atrophic changes are the main reasons for severe vision loss in the natural course of nAMD. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment, the current gold-standard treatment for nAMD, has been shown to improve and maintain the average bestcorrected visual acuity (BCVA) on the basis of monthly intravitreal reinjections.1,2 The effect of VEGF suppression consists of both stopping the growth of new vessels and reducing the exudation from immature vessels. The exudative activity of CNV translates on optical coherence tomography
eovascular age-related macular degeneration (nAMD) is a potentially blinding disorder. The growth of choroidal neovascularization (CNV), the associated exudative activity, and ultimately the devel-
From the *Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland; †Jules Gonin Eye Hospital, Fondation Asile des Aveugles (Foundation Asylum for the blind) , Lausanne, Switzerland. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Irmela Mantel, MD, University Eye Hospital Jules Gonin, 15 Avenue, de France—Case Postale 133, CH-1000 Lausanne 7, Switzerland; e-mail: [email protected]
1195
1196 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
(OCT) into increased retinal thickness, subretinal fluid (SRF), and/or intraretinal cysts. This correlation has allowed for the development of a variable dosing regimen, which is strongly guided by OCT results, with no or little loss of visual efficacy.3–7 However, a proportion of eyes may never reach an exudation-free macula even under monthly anti-VEGF injections.3,4,6 Such persistent or frequently recurrent exudative activity may, in the long run, have a detrimental effect on function and survival of the photoreceptor cells and pigment epithelium. It seems reasonable to assume that persistent or recurrent exudative activity on OCT despite maximal monthly treatment might be associated with poor functional prognosis. However, this has not yet been clearly documented. The aim of this study was to examine the functional and anatomical outcome of nAMD patients with fluid refractory to monthly reinjections with ranibizumab, and to compare the subgroups of treatment-refractory SRF and refractory intraretinal cystic changes. Such knowledge may be useful for the clinician who needs to decide on the need for any treatment modification for eyes with suboptimal treatment response.
Methods This retrospective study was performed in a tertiary referral service for the medical retina (Jules-Gonin University Eye Hospital, Lausanne, Switzerland). The study was approved by the Swiss Federal Department of Health for retrospective analysis of the data and was performed in accordance with the ethical standards in the Declaration of Helsinki. A consecutive series of patients was identified from March 2006 (when ranibizumab became in Switzerland commercially available for treatment of nAMD) to June 2013, with the following inclusion criteria: nAMD with active CNV, age 50 years or older, treatment naïve before initiation of treatment with intravitreal ranibizumab according to a pro re nata (PRN) regimen with monthly visits. The local database was used to systematically identify all consecutive patients with 10 or more injections during the first year. Also required for inclusion into the study was persistent intraretinal fluid or SRF on OCT at each visit over the first 12 months, resulting in monthly treatment being indicated for at least 12 months from baseline. The number of injections was allowed to range from 10 to 13 during the first 12 months. Excluded were eyes with a dry macula at any time during the initial 12 months; eyes with polypoidal choroidal vasculopathy, vitreomacular traction, or any other confounding retinal pathology;
2015 VOLUME 35 NUMBER 6
insufficient fundus image quality; patients undergoing any combination therapy; and patients with missed follow-up visits during the first year. The treatment protocol included three monthly loading doses of intravitreal ranibizumab (0.5 mg), followed by a PRN regimen, based on monthly visits. Retreatment criteria were signs of any intraretinal fluid or SRF on OCT, and/or new hemorrhage on fundus examination, and/or exudation on fluorescein angiography. Baseline examination and all subsequent follow-up visits included as part of our routine clinical practice BCVA on Early Treatment of Diabetic Retinopathy (ETDRS) chart, a slit-lamp examination, measurement of the intraocular pressure, a dilated fundus examination, and an OCT examination (6 radial lines on Stratus OCT3; Carl Zeiss Meditec, Inc, Oberkochen, Germany until December 2008; 128 · 512 cube examination on spectral domain optical coherence tomography Cirrus; Carl Zeiss Meditec, Inc, Oberkochen, Germany from January 2009). Fundus color photography, fundus autofluorescence imaging, fluorescein angiography, and indocyanine green angiography (Topcon TRC-501X; Topcon, Tokyo, Japan) were performed at baseline, at Month 3, and then annually. Additional fundus imaging was performed at the physician’s discretion. Data were collected for gender, laterality, baseline angiographic lesion type, presence of pigment epithelium detachment, choroidal polyps, fibrosis and atrophy, the type of refractory fluid on OCT (intraretinal cystic or subretinal), time to complete resolution of fluid on OCT, BCVA over time until Month 36, number of injections and duration of follow-up, and the presence of fibrosis or atrophy at the last follow-up. If a patient missed the follow-up visit by .2 weeks, the data were censored at the last correct visit. For data analysis, a spreadsheet on Microsoft Excel 2010 and SPSS for Windows software (version 17.0; SPSS, Inc, Chicago, IL) was used. The Student’s t-test and Mann–Whitney U test were used for continuous variables. Chi-square and Fisher’s exact tests were used for categorical variables. A statistical significance level of 0.05 was required.
Results A total of 76 eyes of 74 patients were identified with intraretinal fluid or SRF that was refractory to monthly retreatment with ranibizumab during at least 12 months from treatment initiation (the mean number of injections was 11.4 during the first year, with a range of 10–13). The mean age was 76.8 years (standard deviation, 7.8). There were 57 (77%) female
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
patients and 17 (23%) male patients. The baseline angiographic CNV type was predominantly classic in 20 eyes (26.3%), minimally classic in 16 eyes (21.1%), and occult in 40 eyes (52.6%). Pigment epithelium detachment was present at baseline in 33 eyes (43.4%). The presence of fibrosis or atrophy was found at baseline in 4 (5.3%) and 3 (3.9%), respectively. The mean baseline BCVA was 20/60 Snellen equivalent (60.6 ETDRS letters; standard deviation, 15.3). The baseline characteristics are summarized in Table 1. The mean follow-up was 33.6 months (range, 12–73 months). The follow-up characteristics are summarized in Table 2. The mean number of injections was 27.7 over follow-up (range, 10–52). The treatmentrefractory fluid was subretinal in 45 eyes (59.2%) and intraretinal (cystic changes) in 31 eyes (40.8%). The refractory fluid was subfoveal in 47 eyes (61.8%). In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13–49 months). The BCVA improved by a mean of 7.0, 9.0, 7.9, and 7.9 letters by Month 3, Month 12, Month 24, and Month 36, respectively (Figure 1). An improvement by 15 ETDRS letters or more was found in 30.3, 36.8, and 26.7% of eyes by Month 12, Month 24, and Month 36, respectively (data available for n = 76, 57, and 30 eyes, respectively, each serving as 100%); an improvement of BCVA by 0 letters or more was found in 78.9, 73.7, and 73.3% of eyes, respectively; and a BCVA loss of ,15 letters ETDRS was found in 97.4, 94.7, and 90.0% of eyes, respectively. To eliminate a potential bias because of variable follow-up, the proportion of eyes with ,15 letters loss was calculated on a Kaplan–Meier survival curve. The result revealed a survival rate of 97.4, 95.9, and 89.5% at Month 12,
1197
Month 24, and Month 36, respectively (figure not shown). An additional Kaplan–Meier model for $5 letter improvement from baseline at 2 consecutive visits showed rapid improvement within 3 months in 64% of eyes, and reached 89% within 12 months (figure not shown). A subgroup analysis was performed, comparing eyes with subfoveal (n = 47) versus extrafoveal (n = 29) location of the refractory fluid. No significant difference was found between the two groups in terms of functional outcome. The main subgroup analysis compared eyes with refractory SRF (n = 45) versus eyes with refractory cystic changes (n = 31). Table 1 (baseline) and Table 2 (follow-up) show the characteristics of the 2 groups. There was no difference between these subgroups in terms of age, angiographic type of CNV, associated pigment epithelium detachment, follow-up duration, number of injections, time to resolution, subfoveal location, mean visual acuity change at any time point (Figure 2), or proportions of eyes gaining 15 letters or more and eyes losing ,15 letters ETDRS. However, statistically significant differences between the 2 groups were found for the following outcomes: refractory SRF had a better mean baseline BCVA (20/50 Snellen equivalents = 65.3 ETDRS letters, standard deviation, 11.9) than the group of refractory cysts (20/80 Snellen equivalents = 53.7 letters, standard deviation, 17.2) (P = 0.001). Kaplan–Meier survival curves with the criteria of 10 letters’ loss of BCVA from baseline on at least 2 consecutive visits showed a statistically significant poorer outcome for refractory cystic changes as compared with refractory SRF (Figure 3, P = 0.018, log-rank test). A further difference was found in terms of anatomical outcome: the group of refractory cystic changes showed a significantly
Table 1. Baseline Characteristics of the Study Cohort With nAMD and Fluid Refractory to Monthly Ranibizumab Treatment, According to Fluid Localization (SRF or Intraretinal Cysts)
Eyes, N Age, years (SD) Type of CNV Predominantly classic Minimally classic Occult Associated PED Subfoveal location Atrophy at baseline Fibrosis at baseline Mean baseline VA Snellen equivalent Letters ETDRS (SD)
Refractory SRF
Refractory Intraretinal Cysts
All Patients/Total
Statistical Subgroup Comparison, P
45 76.0 (8.1)
31 78.1 (7.1)
76 76.8 (7.8)
— 0.28 0.24
11 7 27 20 (44.4%) 30 (67%) 2 (4.4%) 1 (2.2%)
9 9 13 13 (41.9%) 17 (55%) 2 (3.2%) 3 (9.7%)
20 (26.3%) 16 (21.1%) 40 (52.6%) 33 (43.4%) 47 (62%) 3 (3.9%) 4 (5.3%)
20/50 65.3 (11.9)
20/80 53.7 (17.2)
20/60 60.6 (15.3)
PED, pigment epithelium detachment; SD, standard deviation; VA, visual acuity. *statistical significance ,0.05.
0.8 0.30 0.99 0.30 0.001
1198 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 6
Table 2. Follow-up Characteristics of the Study Cohort With nAMD and Fluid Refractory to Monthly Ranibizumab Treatment, According to Fluid Localization (SRF or Intraretinal Cysts) Refractory SRF Eyes, N Follow-up duration, months (SD) Number of injections (SD) Resolution of fluid Eyes, n Time to resolution, months (SD) Mean change of VA (SD) 12 months 24 months 36 months Proportion of eyes improving 15 letters or more 12 months 24 months 36 months Proportion of eyes losing ,15 letters 12 months 24 months 36 months Atrophy at last visit Fibrosis at last visit
Refractory Intraretinal Cysts
All Patients/Total
Statistical Subgroup Comparison, P
45 32.4 (15.5)
31 35.3 (14.0)
76 33.6 (14.9)
— 0.41
27.5 (11.1)
28.0 (10.2)
27.7 (10.6)
0.84
12 (48.4%) 22.6 (9.0)
15 (26.7%) 21.2 (8.9)
27 (35.5%) 21.8 (8.8)
0.052 0.69
7.0 (13.8) 7.5 (17.0) 7.4 (17.4)
9.0 (13.5) 7.9 (15.4) 7.9 (14.8)
0.29 0.86 0.83
13 (28.9%, n = 45) 12 (36.4%, n = 33) 3 (21.4%, n = 14)
10 (32.3%, n = 31) 9 (37.5%, n = 24) 5 (31.3%, n = 16)
23 (30.3%, n = 76) 21 (36.8%, n = 57) 8 (26.7%, n = 30)
0.80 0.99 0.69
44 32 14 8 11
30 22 13 13 16
74 54 27 21 27
10.4 (13.3) 8.2 (14.4) 8.6 (11.6)
(97.8%, n = 45) (97.0%, n = 33) (100%, n = 14) (17.8%) (24.4%)
(96.8%, n = 31) (91.7%, n = 24) (81.3%, n = 16) (41.9%) (51.6)
(97.4%, n = 76) (94.7%, n = 57) (90.0%, n = 30) (27.6%) (35.5%)
0.99 0.57 0.23 0.035, OR = 3.34 0.027, OR = 3.30
OR, odds ratio; SD, standard deviation; VA, visual acuity. *statistical significance ,0.05.
higher risk of developing fibrosis (odds ratio, 3.30; 95% confidence interval, 1.24–8.78) and/or atrophy (odds ratio, 3.34; 95% confidence interval, 1.17–9.50) than refractory SRF.
Discussion The randomized controlled multicenter trials MARINA1 and ANCHOR2 showed good functional results with monthly injections of ranibizumab for nAMD. These trials set the goal for visual acuity results of any alternate treatment regimen. The PRN
Fig. 1. Mean change of visual acuity in patients with intraretinal fluid or SRF refractory to monthly retreatment with ranibizumab for nAMD. Error bars represent standard errors.
regimen3–6 and the treat-and-extend regimen8,9 have successfully reduced the mean number of injections, with similar functional results. However, a proportion of eyes still need monthly retreatment in these regimens, according to preset retreatment criteria. The most frequently applied retreatment criteria are based on the OCT results, mainly the presence of intraretinal fluid or SRF,3,6,8 although additional OCT criteria have sometimes been used such as the presence of sub-pigment epithelium fluid or increasing thickness of the central retinal subfield.3,4 The presence of intraretinal fluid or SRF accumulation usually indicates exudative activity of the underlying CNV, and it
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
1199
Fig. 2. Mean change of visual acuity in the subgroups of SRF and intraretinal cysts, refractory to monthly ranibizumab treatment. Error bars represent standard errors, indicated in one direction only for the purpose of better visibility.
is considered potentially harmful to the function and survival of the photoreceptors over time. This assumption becomes evident in the natural course of nAMD, and in treatment regimens with undertreatment of nAMD. Undertreatment may happen in fixed dosing every 3 months only,10,11 or in a PRN regimen with a very low mean number of injections of antiVEGF.12,13 Both are associated with progressive functional loss after the loading dose. This functional loss is believed to be related to multiple exudative recurrences and insufficient VEGF suppression, leading to repetitive periods of ongoing tissue damage and finally, irreversible functional loss.14 However, intraretinal fluid or SRF may also be present despite maximal monthly retreatment with ranibizumab. Clinicians might be concerned that such fluid may lead to functional loss, particularly if persistent over time. The proportion of eyes with persisting fluid despite maximal treatment is unclear. The PrONTO study reported 2 of 40 eyes (5%) that needed monthly retreatment in a PRN regimen,3
Fig. 3. The Kaplan–Meier survival curve of ,10 letters of visual acuity loss for the subgroups of SRF and intraretinal cysts, refractory to monthly ranibizumab treatment.
whereas the CATT trial reported the presence of any fluid (including subretinal pigment epithelium fluid) at the 12-month visit in 53% of patients in the monthly treatment arm.4 In a recent study of the regularity of injection-recurrence intervals, the proportion of eyes with fluid on spectral domain optical coherence tomography at each 4-week visit during 12 months was 25.6%.15 The aim of this study was to describe the functional outcome of this subgroup with refractory fluid despite monthly anti-VEGF injections. The results indicated a surprisingly good, functional long-term outcome, with good initial visual acuity improvement (at Month 3) and maintenance over the course of 3 years, although two thirds of the eyes never reached an exudative-free macula. Even the subgroup of subfoveal location of the refractory fluid showed the same good outcome. This result seemed surprising to us, so we questioned whether there might be a dropout bias due to the worst functional outcomes being lost to followup. However, the Kaplan–Meier survival curve, which takes this problem into account, revealed a proportion of eyes losing more than three lines, which corresponds with the expected overall occurrence of such failure in anti-VEGF treatment of nAMD, as seen in the large Phase III trials.1,2 Therefore, we conclude that intraretinal fluid or SRF refractory to continuous monthly injections is compatible with good functional results. Such encouraging results do not preclude considering an alternate treatment approach for refractory cases although, according to our results, this is probably not always essential for functional outcome. Various approaches of treatment modification have been suggested for refractory cases including increased dosing of the currently available treatments,6,16,17 changing to another anti-VEGF agent,18–20 or using an adjuvant therapy such as photodynamic treatment with visudyne21 and steroids.22
1200 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Some particular situations, such as the association of nAMD with choroidal polypoidal vasculopathy23,24 or vitreomacular traction, may require consideration of an additional or alternative treatment approach.25 In this study, refractory fluid secondary to the underlying polypoidal choroidal vasculopathy or vitreomacular traction was excluded as the patient underwent adjuvant photodynamic treatment or vitrectomy, respectively. The comparison between the subgroups of intraretinal cysts versus SRF revealed a significantly worse functional and anatomical outcome of refractory cysts. Eyes with refractory cysts started with a lower level of baseline BCVA. The 10-letter-loss survival curve showed a statistically significant higher rate of failures in eyes with refractory cysts (the criteria of 10 letters’ loss were chosen because the occurrence of 15 letters’ loss was so rare that it was not statistically useful for this comparison). Furthermore, refractory cysts were significantly associated with a higher risk for atrophy or fibrosis over time, as compared with refractory SRF. This might well be the driving factor for the worse functional outcomes. Previous publications also suggest a more significant impact of cystic retinal changes in AMD. One study measured lower function over cystic changes using microperimetry,26 and two other studies revealed a lower anti-VEGF treatment response associated with cystic changes.27,28 A subanalysis of the CATT trial found that eyes with the residual intraretinal fluid had worse mean BCVA at all time points.29 This study has several limitations. Besides the inherent weaknesses of a retrospective analysis, we acknowledge the variable follow-up duration, the imperfect timing of the monthly indicated reinjections (leading to slightly longer intervals), the absence of a comparison group, and the absence of meaningful data for central retinal thickness over time (i.e., the varying types of OCT machines were used). In addition, the absence of clinical information between the injection and the visit 1 month later does not allow for the differentiation between chronic persistent exudation and early exudative recurrence. In conclusion, nAMD refractory to monthly antiVEGF treatment still allowed well-maintained visual improvement over 3 years, even in subfoveal location. However, the presence of refractory cystic changes on spectral domain optical coherence tomography is associated with a higher risk of developing fibrosis and/or atrophy and losing visual function over time, as compared with refractory SRF. Key words: anti-VEGF, intravitreal injections, neovascular age-related macular degeneration, ranibizumab, refractory fluid.
2015 VOLUME 35 NUMBER 6
References 1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 3. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566–583. 4. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 5. Investigators IS, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399–1411. 6. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013;120:1046–1056. 7. Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 2011;118:663–671. 8. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 2010;117:2134–2140. 9. Abedi F, Wickremasinghe S, Islam AF, et al. Anti-vegf treatment IN neovascular age-related macular degeneration: a treatand-extend protocol over 2 Years. Retina 2014;34:1531–1538. 10. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239–248. 11. Schmidt-Erfurth U, Eldem B, Guymer R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 2011;118:831–839. 12. Dadgostar H, Ventura AA, Chung JY, et al. Evaluation of injection frequency and visual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration. Ophthalmology 2009;116:1740–1747. 13. Gerding H. Treatment of wet AMD with less than 12 injections of ranibizumab per year [in German]. Klin Monbl Augenheilkd 2010;227:294–297. 14. Ersoy L, Ristau T, Kirchhof B, Liakopoulos S. Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2014;252:889–897. 15. Mantel I, Deli A, Iglesias K, Ambresin A. Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2013;251:697–704. 16. Wykoff CC, Brown DM, Chen E, et al. SAVE (Super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related macular degeneration: 1-year results. Ophthalmic Surg Lasers Imaging Retina 2013;44:121–126. 17. Fung AT, Kumar N, Vance SK, et al. Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
18.
19.
20.
21.
22. 23.
of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid ,30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study). Eye 2012;26:1181–1187. 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;33:1605–1612. Wykoff CC, Brown DM, Maldonado ME, Croft DE. Aflibercept treatment for patients with exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections (TURF trial). Br J Ophthalmol 2014;98:951–955. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 2013; 156:29–35.e22. Tozer K, Roller AB, Chong LP, et al. Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents. Ophthalmology 2013;120:2029–2034. Augustin A. Triple therapy for age-related macular degeneration. Retina 2009;29:S8–S11. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy
24.
25.
26.
27.
28.
29.
1201
in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 2012;32:1453–1464. Song MH, Ryu HW, Roh YJ. One-year results of intravitreal ranibizumab with or without photodynamic therapy for polypoidal choroidal vasculopathy. Ophthalmologica 2011;226: 119–126. Mayr-Sponer U, Waldstein SM, Kundi M, et al. Influence of the vitreomacular interface on outcomes of ranibizumab therapy in neovascular age-related macular degeneration. Ophthalmology 2013;120:2620–2629. Sulzbacher F, Kiss C, Kaider A, et al. Correlation of SD-OCT features and retinal sensitivity in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2012;53: 6448–6455. Sulzbacher F, Kiss C, Kaider A, et al. Correlation of OCT characteristics and retinal sensitivity in neovascular agerelated macular degeneration in the course of monthly ranibizumab treatment. Invest Ophthalmol Vis Sci 2013;54: 1310–1315. Golbaz I, Ahlers C, Stock G, et al. Quantification of the therapeutic response of intraretinal, subretinal, and subpigment epithelial compartments in exudative AMD during anti-VEGF therapy. Invest Ophthalmol Vis Sci 2011;52:1599–1605. Jaffe GJ, Martin DF, Toth CA, et al. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2013;120:1860–1870.
N
opment of a fibrovascular scar and/or atrophic changes are the main reasons for severe vision loss in the natural course of nAMD. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment, the current gold-standard treatment for nAMD, has been shown to improve and maintain the average bestcorrected visual acuity (BCVA) on the basis of monthly intravitreal reinjections.1,2 The effect of VEGF suppression consists of both stopping the growth of new vessels and reducing the exudation from immature vessels. The exudative activity of CNV translates on optical coherence tomography
eovascular age-related macular degeneration (nAMD) is a potentially blinding disorder. The growth of choroidal neovascularization (CNV), the associated exudative activity, and ultimately the devel-
From the *Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland; †Jules Gonin Eye Hospital, Fondation Asile des Aveugles (Foundation Asylum for the blind) , Lausanne, Switzerland. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Irmela Mantel, MD, University Eye Hospital Jules Gonin, 15 Avenue, de France—Case Postale 133, CH-1000 Lausanne 7, Switzerland; e-mail: [email protected]
1195
1196 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
(OCT) into increased retinal thickness, subretinal fluid (SRF), and/or intraretinal cysts. This correlation has allowed for the development of a variable dosing regimen, which is strongly guided by OCT results, with no or little loss of visual efficacy.3–7 However, a proportion of eyes may never reach an exudation-free macula even under monthly anti-VEGF injections.3,4,6 Such persistent or frequently recurrent exudative activity may, in the long run, have a detrimental effect on function and survival of the photoreceptor cells and pigment epithelium. It seems reasonable to assume that persistent or recurrent exudative activity on OCT despite maximal monthly treatment might be associated with poor functional prognosis. However, this has not yet been clearly documented. The aim of this study was to examine the functional and anatomical outcome of nAMD patients with fluid refractory to monthly reinjections with ranibizumab, and to compare the subgroups of treatment-refractory SRF and refractory intraretinal cystic changes. Such knowledge may be useful for the clinician who needs to decide on the need for any treatment modification for eyes with suboptimal treatment response.
Methods This retrospective study was performed in a tertiary referral service for the medical retina (Jules-Gonin University Eye Hospital, Lausanne, Switzerland). The study was approved by the Swiss Federal Department of Health for retrospective analysis of the data and was performed in accordance with the ethical standards in the Declaration of Helsinki. A consecutive series of patients was identified from March 2006 (when ranibizumab became in Switzerland commercially available for treatment of nAMD) to June 2013, with the following inclusion criteria: nAMD with active CNV, age 50 years or older, treatment naïve before initiation of treatment with intravitreal ranibizumab according to a pro re nata (PRN) regimen with monthly visits. The local database was used to systematically identify all consecutive patients with 10 or more injections during the first year. Also required for inclusion into the study was persistent intraretinal fluid or SRF on OCT at each visit over the first 12 months, resulting in monthly treatment being indicated for at least 12 months from baseline. The number of injections was allowed to range from 10 to 13 during the first 12 months. Excluded were eyes with a dry macula at any time during the initial 12 months; eyes with polypoidal choroidal vasculopathy, vitreomacular traction, or any other confounding retinal pathology;
2015 VOLUME 35 NUMBER 6
insufficient fundus image quality; patients undergoing any combination therapy; and patients with missed follow-up visits during the first year. The treatment protocol included three monthly loading doses of intravitreal ranibizumab (0.5 mg), followed by a PRN regimen, based on monthly visits. Retreatment criteria were signs of any intraretinal fluid or SRF on OCT, and/or new hemorrhage on fundus examination, and/or exudation on fluorescein angiography. Baseline examination and all subsequent follow-up visits included as part of our routine clinical practice BCVA on Early Treatment of Diabetic Retinopathy (ETDRS) chart, a slit-lamp examination, measurement of the intraocular pressure, a dilated fundus examination, and an OCT examination (6 radial lines on Stratus OCT3; Carl Zeiss Meditec, Inc, Oberkochen, Germany until December 2008; 128 · 512 cube examination on spectral domain optical coherence tomography Cirrus; Carl Zeiss Meditec, Inc, Oberkochen, Germany from January 2009). Fundus color photography, fundus autofluorescence imaging, fluorescein angiography, and indocyanine green angiography (Topcon TRC-501X; Topcon, Tokyo, Japan) were performed at baseline, at Month 3, and then annually. Additional fundus imaging was performed at the physician’s discretion. Data were collected for gender, laterality, baseline angiographic lesion type, presence of pigment epithelium detachment, choroidal polyps, fibrosis and atrophy, the type of refractory fluid on OCT (intraretinal cystic or subretinal), time to complete resolution of fluid on OCT, BCVA over time until Month 36, number of injections and duration of follow-up, and the presence of fibrosis or atrophy at the last follow-up. If a patient missed the follow-up visit by .2 weeks, the data were censored at the last correct visit. For data analysis, a spreadsheet on Microsoft Excel 2010 and SPSS for Windows software (version 17.0; SPSS, Inc, Chicago, IL) was used. The Student’s t-test and Mann–Whitney U test were used for continuous variables. Chi-square and Fisher’s exact tests were used for categorical variables. A statistical significance level of 0.05 was required.
Results A total of 76 eyes of 74 patients were identified with intraretinal fluid or SRF that was refractory to monthly retreatment with ranibizumab during at least 12 months from treatment initiation (the mean number of injections was 11.4 during the first year, with a range of 10–13). The mean age was 76.8 years (standard deviation, 7.8). There were 57 (77%) female
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
patients and 17 (23%) male patients. The baseline angiographic CNV type was predominantly classic in 20 eyes (26.3%), minimally classic in 16 eyes (21.1%), and occult in 40 eyes (52.6%). Pigment epithelium detachment was present at baseline in 33 eyes (43.4%). The presence of fibrosis or atrophy was found at baseline in 4 (5.3%) and 3 (3.9%), respectively. The mean baseline BCVA was 20/60 Snellen equivalent (60.6 ETDRS letters; standard deviation, 15.3). The baseline characteristics are summarized in Table 1. The mean follow-up was 33.6 months (range, 12–73 months). The follow-up characteristics are summarized in Table 2. The mean number of injections was 27.7 over follow-up (range, 10–52). The treatmentrefractory fluid was subretinal in 45 eyes (59.2%) and intraretinal (cystic changes) in 31 eyes (40.8%). The refractory fluid was subfoveal in 47 eyes (61.8%). In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13–49 months). The BCVA improved by a mean of 7.0, 9.0, 7.9, and 7.9 letters by Month 3, Month 12, Month 24, and Month 36, respectively (Figure 1). An improvement by 15 ETDRS letters or more was found in 30.3, 36.8, and 26.7% of eyes by Month 12, Month 24, and Month 36, respectively (data available for n = 76, 57, and 30 eyes, respectively, each serving as 100%); an improvement of BCVA by 0 letters or more was found in 78.9, 73.7, and 73.3% of eyes, respectively; and a BCVA loss of ,15 letters ETDRS was found in 97.4, 94.7, and 90.0% of eyes, respectively. To eliminate a potential bias because of variable follow-up, the proportion of eyes with ,15 letters loss was calculated on a Kaplan–Meier survival curve. The result revealed a survival rate of 97.4, 95.9, and 89.5% at Month 12,
1197
Month 24, and Month 36, respectively (figure not shown). An additional Kaplan–Meier model for $5 letter improvement from baseline at 2 consecutive visits showed rapid improvement within 3 months in 64% of eyes, and reached 89% within 12 months (figure not shown). A subgroup analysis was performed, comparing eyes with subfoveal (n = 47) versus extrafoveal (n = 29) location of the refractory fluid. No significant difference was found between the two groups in terms of functional outcome. The main subgroup analysis compared eyes with refractory SRF (n = 45) versus eyes with refractory cystic changes (n = 31). Table 1 (baseline) and Table 2 (follow-up) show the characteristics of the 2 groups. There was no difference between these subgroups in terms of age, angiographic type of CNV, associated pigment epithelium detachment, follow-up duration, number of injections, time to resolution, subfoveal location, mean visual acuity change at any time point (Figure 2), or proportions of eyes gaining 15 letters or more and eyes losing ,15 letters ETDRS. However, statistically significant differences between the 2 groups were found for the following outcomes: refractory SRF had a better mean baseline BCVA (20/50 Snellen equivalents = 65.3 ETDRS letters, standard deviation, 11.9) than the group of refractory cysts (20/80 Snellen equivalents = 53.7 letters, standard deviation, 17.2) (P = 0.001). Kaplan–Meier survival curves with the criteria of 10 letters’ loss of BCVA from baseline on at least 2 consecutive visits showed a statistically significant poorer outcome for refractory cystic changes as compared with refractory SRF (Figure 3, P = 0.018, log-rank test). A further difference was found in terms of anatomical outcome: the group of refractory cystic changes showed a significantly
Table 1. Baseline Characteristics of the Study Cohort With nAMD and Fluid Refractory to Monthly Ranibizumab Treatment, According to Fluid Localization (SRF or Intraretinal Cysts)
Eyes, N Age, years (SD) Type of CNV Predominantly classic Minimally classic Occult Associated PED Subfoveal location Atrophy at baseline Fibrosis at baseline Mean baseline VA Snellen equivalent Letters ETDRS (SD)
Refractory SRF
Refractory Intraretinal Cysts
All Patients/Total
Statistical Subgroup Comparison, P
45 76.0 (8.1)
31 78.1 (7.1)
76 76.8 (7.8)
— 0.28 0.24
11 7 27 20 (44.4%) 30 (67%) 2 (4.4%) 1 (2.2%)
9 9 13 13 (41.9%) 17 (55%) 2 (3.2%) 3 (9.7%)
20 (26.3%) 16 (21.1%) 40 (52.6%) 33 (43.4%) 47 (62%) 3 (3.9%) 4 (5.3%)
20/50 65.3 (11.9)
20/80 53.7 (17.2)
20/60 60.6 (15.3)
PED, pigment epithelium detachment; SD, standard deviation; VA, visual acuity. *statistical significance ,0.05.
0.8 0.30 0.99 0.30 0.001
1198 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 6
Table 2. Follow-up Characteristics of the Study Cohort With nAMD and Fluid Refractory to Monthly Ranibizumab Treatment, According to Fluid Localization (SRF or Intraretinal Cysts) Refractory SRF Eyes, N Follow-up duration, months (SD) Number of injections (SD) Resolution of fluid Eyes, n Time to resolution, months (SD) Mean change of VA (SD) 12 months 24 months 36 months Proportion of eyes improving 15 letters or more 12 months 24 months 36 months Proportion of eyes losing ,15 letters 12 months 24 months 36 months Atrophy at last visit Fibrosis at last visit
Refractory Intraretinal Cysts
All Patients/Total
Statistical Subgroup Comparison, P
45 32.4 (15.5)
31 35.3 (14.0)
76 33.6 (14.9)
— 0.41
27.5 (11.1)
28.0 (10.2)
27.7 (10.6)
0.84
12 (48.4%) 22.6 (9.0)
15 (26.7%) 21.2 (8.9)
27 (35.5%) 21.8 (8.8)
0.052 0.69
7.0 (13.8) 7.5 (17.0) 7.4 (17.4)
9.0 (13.5) 7.9 (15.4) 7.9 (14.8)
0.29 0.86 0.83
13 (28.9%, n = 45) 12 (36.4%, n = 33) 3 (21.4%, n = 14)
10 (32.3%, n = 31) 9 (37.5%, n = 24) 5 (31.3%, n = 16)
23 (30.3%, n = 76) 21 (36.8%, n = 57) 8 (26.7%, n = 30)
0.80 0.99 0.69
44 32 14 8 11
30 22 13 13 16
74 54 27 21 27
10.4 (13.3) 8.2 (14.4) 8.6 (11.6)
(97.8%, n = 45) (97.0%, n = 33) (100%, n = 14) (17.8%) (24.4%)
(96.8%, n = 31) (91.7%, n = 24) (81.3%, n = 16) (41.9%) (51.6)
(97.4%, n = 76) (94.7%, n = 57) (90.0%, n = 30) (27.6%) (35.5%)
0.99 0.57 0.23 0.035, OR = 3.34 0.027, OR = 3.30
OR, odds ratio; SD, standard deviation; VA, visual acuity. *statistical significance ,0.05.
higher risk of developing fibrosis (odds ratio, 3.30; 95% confidence interval, 1.24–8.78) and/or atrophy (odds ratio, 3.34; 95% confidence interval, 1.17–9.50) than refractory SRF.
Discussion The randomized controlled multicenter trials MARINA1 and ANCHOR2 showed good functional results with monthly injections of ranibizumab for nAMD. These trials set the goal for visual acuity results of any alternate treatment regimen. The PRN
Fig. 1. Mean change of visual acuity in patients with intraretinal fluid or SRF refractory to monthly retreatment with ranibizumab for nAMD. Error bars represent standard errors.
regimen3–6 and the treat-and-extend regimen8,9 have successfully reduced the mean number of injections, with similar functional results. However, a proportion of eyes still need monthly retreatment in these regimens, according to preset retreatment criteria. The most frequently applied retreatment criteria are based on the OCT results, mainly the presence of intraretinal fluid or SRF,3,6,8 although additional OCT criteria have sometimes been used such as the presence of sub-pigment epithelium fluid or increasing thickness of the central retinal subfield.3,4 The presence of intraretinal fluid or SRF accumulation usually indicates exudative activity of the underlying CNV, and it
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
1199
Fig. 2. Mean change of visual acuity in the subgroups of SRF and intraretinal cysts, refractory to monthly ranibizumab treatment. Error bars represent standard errors, indicated in one direction only for the purpose of better visibility.
is considered potentially harmful to the function and survival of the photoreceptors over time. This assumption becomes evident in the natural course of nAMD, and in treatment regimens with undertreatment of nAMD. Undertreatment may happen in fixed dosing every 3 months only,10,11 or in a PRN regimen with a very low mean number of injections of antiVEGF.12,13 Both are associated with progressive functional loss after the loading dose. This functional loss is believed to be related to multiple exudative recurrences and insufficient VEGF suppression, leading to repetitive periods of ongoing tissue damage and finally, irreversible functional loss.14 However, intraretinal fluid or SRF may also be present despite maximal monthly retreatment with ranibizumab. Clinicians might be concerned that such fluid may lead to functional loss, particularly if persistent over time. The proportion of eyes with persisting fluid despite maximal treatment is unclear. The PrONTO study reported 2 of 40 eyes (5%) that needed monthly retreatment in a PRN regimen,3
Fig. 3. The Kaplan–Meier survival curve of ,10 letters of visual acuity loss for the subgroups of SRF and intraretinal cysts, refractory to monthly ranibizumab treatment.
whereas the CATT trial reported the presence of any fluid (including subretinal pigment epithelium fluid) at the 12-month visit in 53% of patients in the monthly treatment arm.4 In a recent study of the regularity of injection-recurrence intervals, the proportion of eyes with fluid on spectral domain optical coherence tomography at each 4-week visit during 12 months was 25.6%.15 The aim of this study was to describe the functional outcome of this subgroup with refractory fluid despite monthly anti-VEGF injections. The results indicated a surprisingly good, functional long-term outcome, with good initial visual acuity improvement (at Month 3) and maintenance over the course of 3 years, although two thirds of the eyes never reached an exudative-free macula. Even the subgroup of subfoveal location of the refractory fluid showed the same good outcome. This result seemed surprising to us, so we questioned whether there might be a dropout bias due to the worst functional outcomes being lost to followup. However, the Kaplan–Meier survival curve, which takes this problem into account, revealed a proportion of eyes losing more than three lines, which corresponds with the expected overall occurrence of such failure in anti-VEGF treatment of nAMD, as seen in the large Phase III trials.1,2 Therefore, we conclude that intraretinal fluid or SRF refractory to continuous monthly injections is compatible with good functional results. Such encouraging results do not preclude considering an alternate treatment approach for refractory cases although, according to our results, this is probably not always essential for functional outcome. Various approaches of treatment modification have been suggested for refractory cases including increased dosing of the currently available treatments,6,16,17 changing to another anti-VEGF agent,18–20 or using an adjuvant therapy such as photodynamic treatment with visudyne21 and steroids.22
1200 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Some particular situations, such as the association of nAMD with choroidal polypoidal vasculopathy23,24 or vitreomacular traction, may require consideration of an additional or alternative treatment approach.25 In this study, refractory fluid secondary to the underlying polypoidal choroidal vasculopathy or vitreomacular traction was excluded as the patient underwent adjuvant photodynamic treatment or vitrectomy, respectively. The comparison between the subgroups of intraretinal cysts versus SRF revealed a significantly worse functional and anatomical outcome of refractory cysts. Eyes with refractory cysts started with a lower level of baseline BCVA. The 10-letter-loss survival curve showed a statistically significant higher rate of failures in eyes with refractory cysts (the criteria of 10 letters’ loss were chosen because the occurrence of 15 letters’ loss was so rare that it was not statistically useful for this comparison). Furthermore, refractory cysts were significantly associated with a higher risk for atrophy or fibrosis over time, as compared with refractory SRF. This might well be the driving factor for the worse functional outcomes. Previous publications also suggest a more significant impact of cystic retinal changes in AMD. One study measured lower function over cystic changes using microperimetry,26 and two other studies revealed a lower anti-VEGF treatment response associated with cystic changes.27,28 A subanalysis of the CATT trial found that eyes with the residual intraretinal fluid had worse mean BCVA at all time points.29 This study has several limitations. Besides the inherent weaknesses of a retrospective analysis, we acknowledge the variable follow-up duration, the imperfect timing of the monthly indicated reinjections (leading to slightly longer intervals), the absence of a comparison group, and the absence of meaningful data for central retinal thickness over time (i.e., the varying types of OCT machines were used). In addition, the absence of clinical information between the injection and the visit 1 month later does not allow for the differentiation between chronic persistent exudation and early exudative recurrence. In conclusion, nAMD refractory to monthly antiVEGF treatment still allowed well-maintained visual improvement over 3 years, even in subfoveal location. However, the presence of refractory cystic changes on spectral domain optical coherence tomography is associated with a higher risk of developing fibrosis and/or atrophy and losing visual function over time, as compared with refractory SRF. Key words: anti-VEGF, intravitreal injections, neovascular age-related macular degeneration, ranibizumab, refractory fluid.
2015 VOLUME 35 NUMBER 6
References 1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 3. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566–583. 4. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 5. Investigators IS, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399–1411. 6. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013;120:1046–1056. 7. Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 2011;118:663–671. 8. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 2010;117:2134–2140. 9. Abedi F, Wickremasinghe S, Islam AF, et al. Anti-vegf treatment IN neovascular age-related macular degeneration: a treatand-extend protocol over 2 Years. Retina 2014;34:1531–1538. 10. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239–248. 11. Schmidt-Erfurth U, Eldem B, Guymer R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 2011;118:831–839. 12. Dadgostar H, Ventura AA, Chung JY, et al. Evaluation of injection frequency and visual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration. Ophthalmology 2009;116:1740–1747. 13. Gerding H. Treatment of wet AMD with less than 12 injections of ranibizumab per year [in German]. Klin Monbl Augenheilkd 2010;227:294–297. 14. Ersoy L, Ristau T, Kirchhof B, Liakopoulos S. Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2014;252:889–897. 15. Mantel I, Deli A, Iglesias K, Ambresin A. Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2013;251:697–704. 16. Wykoff CC, Brown DM, Chen E, et al. SAVE (Super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related macular degeneration: 1-year results. Ophthalmic Surg Lasers Imaging Retina 2013;44:121–126. 17. Fung AT, Kumar N, Vance SK, et al. Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management
OUTCOME OF REFRACTORY NEOVASCULAR AMD GIANNIOU ET AL
18.
19.
20.
21.
22. 23.
of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid ,30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study). Eye 2012;26:1181–1187. 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;33:1605–1612. Wykoff CC, Brown DM, Maldonado ME, Croft DE. Aflibercept treatment for patients with exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections (TURF trial). Br J Ophthalmol 2014;98:951–955. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 2013; 156:29–35.e22. Tozer K, Roller AB, Chong LP, et al. Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents. Ophthalmology 2013;120:2029–2034. Augustin A. Triple therapy for age-related macular degeneration. Retina 2009;29:S8–S11. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy
24.
25.
26.
27.
28.
29.
1201
in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 2012;32:1453–1464. Song MH, Ryu HW, Roh YJ. One-year results of intravitreal ranibizumab with or without photodynamic therapy for polypoidal choroidal vasculopathy. Ophthalmologica 2011;226: 119–126. Mayr-Sponer U, Waldstein SM, Kundi M, et al. Influence of the vitreomacular interface on outcomes of ranibizumab therapy in neovascular age-related macular degeneration. Ophthalmology 2013;120:2620–2629. Sulzbacher F, Kiss C, Kaider A, et al. Correlation of SD-OCT features and retinal sensitivity in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2012;53: 6448–6455. Sulzbacher F, Kiss C, Kaider A, et al. Correlation of OCT characteristics and retinal sensitivity in neovascular agerelated macular degeneration in the course of monthly ranibizumab treatment. Invest Ophthalmol Vis Sci 2013;54: 1310–1315. Golbaz I, Ahlers C, Stock G, et al. Quantification of the therapeutic response of intraretinal, subretinal, and subpigment epithelial compartments in exudative AMD during anti-VEGF therapy. Invest Ophthalmol Vis Sci 2011;52:1599–1605. Jaffe GJ, Martin DF, Toth CA, et al. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2013;120:1860–1870.
