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ORIGINAL CLINICAL STUDY Predictability of Recalcitrance in Neovascular Age-Related Macular Degeneration With Indocyanine Green Angiography Ryan B. Rush, MD*Þþ and Sloan W. Rush, MDÞþ Purpose: This study aimed to evaluate the utility of indocyanine green (ICG) angiography in predicting recalcitrance in neovascular age-related macular degeneration (nAMD). Design: A retrospective case series. Methods: The charts of treatment-naive subjects with nAMD undergoing antiYvascular endothelial growth factor (anti-VEGF) therapy during a 6-month period were retrospectively reviewed. The study group consisted of subjects with persistent retinal edema on optical coherence tomography (OCT) despite 6 consecutive monthly anti-VEGF injections. The control group was age-matched to the study group and consisted of subjects who demonstrated complete resolution of retinal edema on OCT after 3 or fewer monthly anti-VEGF injections. Results: There were 42 study cases and 42 controls included in the analysis. The baseline visual acuity, central macular thickness on OCT, and choroidal neovascularization (CNV) surface area on ICG angiography were statistically similar between the study and control groups. The CNV surface area on ICG angiography 2 months after starting consecutive monthly anti-VEGF injections increased from a baseline of 1.78 T 0.86 to 2.66 T 0.92 mm2 in the study group (P = 0.008) and decreased from a baseline of 1.94 T 0.97 to 1.12 T 0.05 mm2 in the control group (P = 0.04); this change in CNV size on ICG angiography from baseline to 2-month follow-up was statistically significant between the study and control groups (P G 0.0001). Conclusions: Change in CNV surface area on ICG angiography can predict which subjects with nAMD are likely to have persistent retinal edema on OCT after 6 or more consecutive monthly anti-VEGF injections. Key Words: indocyanine green angiography, macular degeneration, recalcitrance (Asia Pac J Ophthalmol 2015;4: 187Y190) P ersistent retinal edema on optical coherence tomography (OCT) was found in more than 50% of patients with neovascular age-related macular degeneration (nAMD) undergoing ranibizumab (Lucentis; Genetech, Inc, South San Francisco, Calif ) and bevacizumab (Avastin; Genetech, Inc) therapy after 1 and 2 years in the Comparison of Age-related Macular Degeneration Treatments Trials.1,2 Patients with persistent retinal edema despite consecutive monthly antiYvascular endothelial growth factor (anti-VEGF) injections may be considered to have treatmentresistant choroidal neovascularization (CNV), and several strategies have evolved to deal with the following clinical situations: injections more frequently than every 4 weeks,3 higher anti-VEGF From the *Southwest Retina Specialists; †Panhandle Eye Group; and ‡Department of Surgery, Texas Tech University Health Science Center, Amarillo, TX. Received for publication November 2, 2014; accepted January 16, 2015. The authors have no funding or conflicts of interest to declare. Reprints: Ryan B. Rush, MD, Southwest Retina Specialists, 7411 Wallace Blvd., Amarillo, TX, 79106. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000111 Asia-Pacific Journal of Ophthalmology & dosages,4 anti-VEGF combined with photodynamic therapy,5 and changing anti-VEGF drugs. Several retrospective studies6Y10 and 1 prospective study11 have reported that switching from ranibizumab or bevacizumab to aflibercept (VEGF-Trap Eye/Eylea; Regeneron, Tarrytown, NY) can reduce or eliminate persistent retinal edema on OCT in patients with recalcitrant nAMD. Recently, Rush et al12 described the clinical utility of indocyanine green (ICG) angiography in subjects with nAMD undergoing bevacizumab therapy. However, subjects switching anti-VEGF drugs or receiving combination therapy during the 12-month study interval were purposefully excluded from that study, which resulted in the removal of the most treatmentresistant subjects from the analysis. Therefore, it remains unknown how CNV size on ICG angiography changes in those subjects with nAMD recalcitrant to anti-VEGF therapy. The purpose of this study was to determine if change in CNV size on ICG angiography early in the course of treatment can predict the persistence of retinal edema on OCT after 6 consecutive monthly anti-VEGF injections in subjects with nAMD. MATERIALS AND METHODS The Southwest Retina Specialists Institutional Review Board (IORG0007600/IRB00009122) approved this retrospective medical record review of patients with nAMD treated from March 2011 to March 2014 at a single private-practice institution. All research constituents observed the tenets of the Declaration of Helsinki and were directed in agreement with human research regulations and standards. The inclusion criteria were as follows: (1) 55 years or older; (2) a diagnosis of treatment-naive subfoveal nAMD confirmed by clinical examination, OCT, fluorescein angiography (FA), and ICG angiography; (3) baseline Snellen bestcorrected visual acuity (BCVA) between 20/25 and 20/200; (4) a 6-month study period fully documented with BCVA, examination details, OCT, FA, and ICG angiography; (5) ICG angiography that must have been performed at baseline, 2month follow-up, and 6-month follow-up; and (6) a pro re nata regimen adhered to as described later. The exclusion criteria were as follows: (1) macular photocoagulation, photodynamic therapy, or an intravitreal injection other than anti-VEGF therapy was given to the study eye during the study period; (2) an ocular media opacity was affecting BCVA or obstructing imaging acquisition; (3) intraocular surgery was performed during the study period or within 3 months before subject enrollment; (4) retinal diseases other than nAMD (epiretinal membrane, polypoidal choroidal vasculopathy, diabetic retinopathy, etc), uncontrolled glaucoma, or active uveitis were present at enrollment or developed during the study period; (5) a previous vitrectomy had been performed at any time to the study eye; and (6) the CNV margins were unable to be measured by ICG angiography (absence of a distinct CNV complex and/or ‘‘hot’’ spots without distinguishable margins). Polypoidal choroidal vasculopathy was defined as the presence of 1 or multiple Volume 4, Number 4, July/August 2015 www.apjo.org Copyright © 2015 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. 187 Rush and Rush Asia-Pacific Journal of Ophthalmology focal areas of hyperfluorescence from inner choroidal vessels within the first 6 minutes after injection of ICG with or without an associated branching vascular network and without an associated classic or occult CNV complex.13 Baseline examinations included BCVA, slit-lamp assessment of the anterior segments and posterior segments, OCT, FA, as well as ICG angiography. All subjects received a loading dose of 3 consecutive monthly anti-VEGF injections, followed by consecutive monthly injections until the macula was dry (without intraretinal or subretinal fluid) on OCT. Once this measure was achieved, the injection was deferred and the patient returned for follow-up 4 weeks later. If retinal edema on OCT recurred or macular hemorrhage developed after injection deferral, anti-VEGF treatment was resumed. The subjects failing to achieve a dry macula on OCT after 6 consecutive monthly anti-VEGF injections were put into the study group. The subjects achieving a dry macula on OCT after the 3 consecutive monthly anti-VEGF loading doses were put into the control group. The subjects in the study group were permitted to change anti-VEGF medications so long as they continued receiving consecutive monthly injections without ever attaining a dry macula on OCT. The OCT, FA, and ICG angiography procedures were performed using the Heidelberg Spectralis system (Heidelberg, Germany). The detection of retinal edema and the central macular thickness were determined by OCT. The surface areaYmeasuring software of the Heidelberg Spectralis was used to determine CNV size with ICG angiography, and this technique in the setting of nAMD has been described in a previous study.12 Briefly, early-frame to midframe ICG angiography images were viewed, and a test image was chosen for CNV size analysis. The CNV margins were manually encircled using the ‘‘Inlay’’ function, and the surface area was then computed. Sideby-side OCT and FA images of the ICG angiography test image were permitted to establish the precise location of the CNV. All the CNV measurements on ICG angiography were independently evaluated by 2 masked observers (R.B.R. and S.W.R.). If CNV size was not within 10% between the 2 masked observers, the subject was excluded from the analysis. Outcome Measures and Statistical Analysis The primary outcome of the study was a change in CNV surface area on ICG angiography from baseline to 2-month follow-up in the study and control groups. Statistical calculations were performed using the JMP software package from the SAS Institute. Snellen BCVA was converted into a logarithm of the minimal angle of resolution (logMAR) for the statistical analysis. Numerical means were compared using 1-way analysis of the variance whereas nominal variables were compared using & Volume 4, Number 4, July/August 2015 W2 and likelihood ratios where appropriate. A probability of less than 0.05 was considered statistically significant. RESULTS There were 47 study cases that met the criteria for inclusion. Of these 47 cases, 5 were disqualified from analysis because of a discordance of more than 10% for the CNV size between the masked observers, thereby allowing for an interobserver agreement rate of 89.3% (42/47) for the study group. There were 42 control cases age-matched (T3 years) to the 42 study subjects. The baseline characteristics of the study group were as follows: the mean T SD age was 79.1 T 8.6 with 52% male (22/42) and 48% female (20/42). The lens status was pseudophakic for 67% (28/42) and phakic for 33% (14/42). The study group’s baseline BCVA was 0.55 T 0.24 logMAR (Snellen visual acuity, 20/71), central macular thickness on OCT was 431.0 T 88.6 Km, and CNV surface area on ICG angiography was 1.78 T 0.86 mm2. There were 30.9% (13/42) of study subjects with classic/predominantly classic, 28.5% (12/42) with minimally classic, and 40.4% (17/42) with occult CNV on baseline FA. The baseline characteristics of the control group were as follows: the mean T SD age was 78.4 T 8.1 with 57% male (24/42) and 43% female (18/42). The lens status was pseudophakic for 62% (26/42) and phakic for 38% (16/42). The control group’s baseline BCVA was 0.50 T 0.22 logMAR (Snellen visual acuity, 20/63), central macular thickness on OCT was 403.4 T 98.2 Km, and CNV surface area on ICG angiography was 1.94 T 0.97 mm2. There were 28.5% (12/42) of control subjects with classic/ predominantly classic, 23.8% (10/42) with minimally classic, and 47.6% (20/42) with occult CNV on baseline FA. There were no significant differences in any of the baseline characteristics between the groups. The study group was treated with the following anti-VEGF medications during the study period: 22 with bevacizumab alone, 6 with aflibercept alone, 3 with ranibizumab alone, and 11 with more than 1 anti-VEGF agent. The control group was treated with the following anti-VEGF medications during the study period: 27 with bevacizumab alone, 9 with aflibercept alone, and 6 with ranibizumab alone. The mean T SD number of anti-VEGF injections delivered during the 6-month study period was 4.1 T 0.8 in the control group. The CNV surface area on ICG angiography at 2-month follow-up was 2.66 T 0.92 mm2 in the study group, which was significantly enlarged from the baseline value (P = 0.008). The CNV surface area on ICG angiography at 2-month followup was 1.12 T 1.05 mm2 in the control group, which was significantly reduced from the baseline value (P = 0.04). The change in CNV size on ICG angiography from baseline to 2month follow-up was significantly different between the study and control groups (P G 0.0001). There were 76.2% (32/42) of FIGURE 1. The treatment-naive baseline FA (A), ICG angiography (B), and OCT (C) images of a 79-year-old study patient with baseline Snellen visual acuity of 20/60. The CNV is encircled in white with the corresponding surface area calculation on the ICG angiography image. 188 www.apjo.org * 2015 Asia Pacific Academy of Ophthalmology Copyright © 2015 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. Asia-Pacific Journal of Ophthalmology & Volume 4, Number 4, July/August 2015 Recalcitrant Macular Degeneration FIGURE 2. The FA (A), ICG angiography (B), and OCT (C) images of the same patient presented in Figure 1 at the 2-month follow-up evaluation after receiving 2 bevacizumab injections. Notice that the CNV size on ICG angiography has enlarged by more than 33% from baseline. The Snellen visual acuity remains 20/60. subjects with enlarged CNV size and 64.2% (27/42) of subjects with more than 33% enlargement in CNV size on ICG angiography in the study group at 2-month follow-up; in comparison, there were 19.0% (8/42) of subjects with enlarged CNV size, and 7.1% (3/42) of subjects with more than 33% enlargement in CNV size on ICG angiography in the control group at 2-month follow-up. These differences between the groups were significant (P = 0.022 and P = 0.005, respectively). The study group’s BCVA was 0.48 T 0.19 logMAR (Snellen visual acuity, 20/60), central macular thickness on OCT was 363.6 T 75.6 Km, and CNV surface area on ICG angiography was 2.82 T 1.16 mm2 at the end of the 6-month study period. The final BCVA was not significantly different from the baseline value (P = 0.39), but the final central macular thickness on OCT was significantly reduced from the baseline value (P = 0.035), and the final CNV size on ICG angiography was significantly larger than the baseline value (P = 0.002) in the study group. The control group’s BCVA was 0.30 T 0.16 logMAR (Snellen visual acuity, 20/39), central macular thickness on OCT was 278.5 T 68.9 Km, and CNV surface area on ICG angiography was 0.88 T 0.84 mm 2 at the end of the 6-month study period. The control group’s final BCVA, central macular thickness on OCT, and CNV size on ICG angiography were significantly improved from baseline (P G 0.001 for all). See Figures 1 to 3 for a case example from the study group. DISCUSSION The structure of CNV on ICG angiography may vary substantially according to the stage of development or regression.14,15 The Heidelberg Spectralis confocal scanning laser ophthalmoscope technology provides high-quality images that allow clinicians to detect and precisely measure CNV surface area on ICG angiography regardless of the CNV stage; similar to a previous report12 using this method of CNV size determination, masked observers in this study were also able to agree on more than 80% of test images within 10% of the lesion size. This high interobserver concordance rate supports the notion that the CNV measurement technique used by this study provides a less subjective and more reproducible method compared with CNV classification systems of the past that graded hyperfluorescence and dye leakage with digital videoangiography.16Y23 This is the first study to evaluate the utility of ICG angiography as a clinical tool to predict the likelihood of future recalcitrance in subjects with nAMD early in the course of treatment. The most significant finding of this study is the enlargement in CNV size on ICG angiography observed from baseline to 2 months in the study group compared with the reduction in CNV size on ICG angiography from baseline to 2 months in the control group. A previous study12 demonstrated an increase of 33% or more in CNV size on ICG angiography from baseline to 2-month follow-up in just 5.7% of their overall cohort of subjects with nAMD; the overall study population in that study had a decrease in CNV size on ICG angiography from 1.9 T 2.5 mm2 at baseline to 1.66 T 2.11 mm2 at 2-month follow-up. Similar to this previous study, the control group of our current study had an increase of 33% or more in CNV size on ICG angiography from baseline to 2-month follow-up in a very small number of cases (7.1%). However, most subjects (64.2%) in the study group had an increase of 33% or more in CNV size on ICG angiography from baseline to 2-month follow-up, and this was statistically significant compared with the control group. Therefore, the typical subject with nonrecalcitrant nAMD undergoing anti-VEGF therapy has a decrease in CNV size from baseline to 2-month follow-up and rarely has an increase of 33% or more in CNV size on ICG angiography from baseline to 2-month follow-up. The clinical application of this finding is as follows: subjects demonstrating an enlargement in CNV size on ICG angiography from baseline to 2-month FIGURE 3. The FA (A), ICG angiography (B), and OCT (C) images of the same patient presented in Figures 1 and 2 after receiving 6 consecutive monthly bevacizumab injections. Notice that the CNV size on ICG angiography has further increased and subretinal fluid on OCT persists. The Snellen visual acuity has decreased to 20/70. The pronounced enlargement in CNV surface area on ICG angiography from baseline to 2-month follow-up predicted this subject’s recalcitrance to bevacizumab therapy. * 2015 Asia Pacific Academy of Ophthalmology www.apjo.org Copyright © 2015 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. 189 Asia-Pacific Journal of Ophthalmology Rush and Rush follow-up, especially when an increase of 33% or more occurs, are statistically likely to be recalcitrant to anti-VEGF therapy with persistent retinal edema on OCT despite 6 or more consecutive monthly injections. Having now identified these treatment-resistant subjects at a very early stage in the course of treatment, the clinician may then consider alternative treatment options such as combination therapy, a switch in antiVEGF medication, higher-dosage ranibizumab, or anti-VEGF therapy more frequently than once per month at a stage sooner than would otherwise have been considered to improve longterm outcomes for this challenging subgroup. Weaknesses of this study include the retrospective collection of data, the use of logMAR visual acuity, the small number of study subjects, limited follow-up, and the observer-dependent determination of CNV size on ICG angiography. The information in our study subjects’ medical records was not sufficient to match the 2 groups for ‘‘maturity’’ of CNV by symptom duration before treatment initiation. It should be cautioned that the results of this study may not apply to patients with CNV presenting as ‘‘hot spots’’ without distinguishable margins on ICG angiography; the subjects with hot spots in this study often had polypoidal choroidal vasculopathy and were excluded from analysis per the exclusion criteria. In summary, our study demonstrated that a change in CNV surface area on ICG angiography from baseline to 2-month followup can predict which subjects with nAMD are likely to have persistent retinal edema on OCT at 6-month follow-up despite consecutive monthly anti-VEGF injections during that period. The clinician should be alerted to the likelihood of recalcitrance at an early stage in the treatment course of nAMD to consider alternative treatment options sooner when CNV size enlarges from baseline to 2-month follow-up, particularly if 33% or more. 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