COMPARISON OF INTRAVITREAL RANIBIZUMAB IN PHAKIC AND PSEUDOPHAKIC NEOVASCULAR AGE-RELATED MACULAR DEGENERATION PATIENTS WITH GOOD BASELINE VISUAL ACUITY ABDULLAH OZKAYA, MD,* ZEYNEP ALKIN, MD,* AHMET T. YAZICI, MD,* AHMET DEMIROK, MD† Purpose: To compare the efficacy of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration between phakic and pseudophakic eyes with visual acuity $0.5 Snellen equivalent. Methods: This was a retrospective, interventional, comparative study. The newly diagnosed neovascular age-related macular degeneration patients with visual acuity of $0.5 Snellen equivalent were included in the study. The patients were divided into two subgroups: phakic group and pseudophakic. All patients received three consecutive monthly intravitreal ranibizumab injections, and then, reinjection was performed as needed. Patients were examined monthly, and the data at the baseline, at Months 3, 6, 9, and 12 were evaluated. The changes in visual acuity, central retinal thickness, and the number of injections were compared between the groups. Results: The study included 96 eyes of 96 patients (56 phakic and 40 pseudophakic). Mean Snellen visual acuity at the baseline, at Months 3, 6, 9, and 12 was 0.56 ± 0.09, 0.64 ± 0.15, 0.62 ± 0.21, 0.60 ± 0.22, and 0.61 ± 0.20 for the phakic group; and 0.55 ± 0.08, 0.63 ± 0.14, 0.60 ± 0.13, 0.58 ± 0.14, and 0.59 ± 0.13 for the pseudophakic group, respectively. The change in mean visual acuity and central retinal thickness at the study visits was not statistically significant between the 2 groups (P . 0.05 for all). Mean injection number at Month 12 was 4.5 and 4.3 in the phakic and pseudophakic group, respectively (P = 0.5). Conclusion: Intravitreal ranibizumab treatment on an as-needed treatment regimen is effective in preserving vision and improving central retinal thickness in both the phakic and pseudophakic group of neovascular age-related macular degeneration patients with good baseline visual acuity. RETINA 34:853–859, 2014
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eovascular age-related macular degeneration (nAMD) is a major cause of visual loss among the elderly population in developed countries.1,2 Before the introduction of intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy for
nAMD, only prevention for visual loss might have been achieved in a limited number of patients with different treatment options like laser photocoagulation, vitreoretinal surgery, and photodynamic therapy.3–9 The introduction of bevacizumab (full-length antibody against VEGF-A) and ranibizumab (Fab part of antibody against VEGF-A) have led to the prevention of the visual acuity loss in most of the patients.10,11 The pivotal multicenter studies like MARINA, ANCHOR, PRONTO, EXCITE, and CATT showed that ranibizumab is effective to prevent visual acuity loss in up to 95% of the patients and is effective to
From the *Beyoglu Eye Training and Research Hospital, Istanbul, Turkey; and †Department of Ophthalmology, Medeniyet University, Istanbul, Turkey. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Abdullah Ozkaya, MD, Beyoglu Eye Training and Research Hospital, Bereketzade Camii Sok, 34421 Istanbul, Turkey; e-mail: [email protected]
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make an improvement in the visual acuity in up to 40% of the patients.11–15 However, these large studies did not include the patients with a Snellen visual acuity of 0.5 or better. Lately, some studies about the efficacy of ranibizumab treatment on an as-needed regimen were reported in this group of patients.16–22 However, except one of them,19 these studies were mainly focused on visual and anatomical results. In addition, there are only two studies to date regarding the association between IVR injection and lens status.23,24 One of these studies is a metaanalysis of the patient data from ANCHOR and MARINA studies, so this study included the nAMD patients with visual acuity between 20/320 and 20/4023, and the other study did not have a visual acuity threshold criterion.24 To the best of our knowledge, there are no reports regarding the association between lens status and efficacy of IVR in nAMD patients with a good baseline visual acuity. In this study, we aimed to compare the efficacy of IVR on an as-needed regimen between phakic and pseudophakic nAMD patients with a Snellen visual acuity $0.5. Methods In this retrospective interventional comparative study, we reviewed the records of the nAMD patients who had a baseline Snellen visual acuity $0.5 and treated with intravitreal ranibizumab injection on an as-needed treatment regimen between January 2010 and January 2011. A written informed consent for the intravitreal injections was obtained from all patients before the treatment, and the study adhered to the tenets of the Declaration of Helsinki. To be included in the study, each patient was required to have all the following criteria: age $50 years, a best-corrected Snellen visual acuity (BCVA) $0.5, to be newly diagnosed as nAMD and treatment naive, and a minimum follow-up time of 12 months. Patients were not included in the study if they had a retinal disease other than nAMD (e.g., diabetic retinopathy, retinal vein occlusion) or if they had received previous intravitreal injection therapy, or photodynamic therapy for nAMD, or if they had been diagnosed as polypoidal choroidal vasculopathy, or retinal angiomatous proliferation. Also, the phakic patients who needed cataract surgery during the follow-up time and underwent cataract surgery were excluded from the study. The patients were divided into two groups according to their lens state, which were phakic and pseudophakic groups when the patients were initially diagnosed as nAMD. The pseudophakic patients who were
included in the study were chosen among the patients who had undergone uneventful phacoemulsification surgery before the study and had intact posterior capsules. Data collected from the patients’ records included age, gender, choroidal neovascularization (CNV) type (predominantly classic or minimal classic/occult), greatest lesion diameter of CNV, BCVA, and central retinal thickness (CRT) at the baseline, at Months 3, 6, 9, and 12. Reinjection numbers at Month 12 were also recorded. All patients underwent a standardized examination including measurement of BCVA through the Early Treatment Diabetic Retinopathy Study chart at 4 m, slit-lamp biomicroscopy, measurement of intraocular pressure (IOP) through applanation tonometry, and biomicroscopic fundus examination. Fundus photography, fluorescein angiography (HRA-2; Heidelberg Engineering, Heidelberg, Germany), and optical coherence tomography (OCT) (Stratus OCT; Carl Zeiss Meditec Inc, Dublin, CA) were performed before treatment. All examinations were repeated monthly, except fluorescein angiography. Fluorescein angiography was repeated only when the cause of visual acuity deterioration could not be clarified with the other methods. Optical coherence tomography was used for detecting subretinal fluid and measurement of CRT. Central retinal thickness, defined as the mean thickness of the neurosensory retina in a central 1-mm-diameter area, was computed using OCT mapping software generated by the device. All injections were performed under sterile conditions after topical anesthesia and 10% povidone–iodine (Betadine; Purdue Pharma, Stamford, CT) scrub was used on the lids and lashes, and 5% povidone–iodine was administered on the conjunctival sac. Intravitreal ranibizumab was injected through the pars plana at 3.5 mm to 4 mm to the limbus with a 27-gauge needle. Patients were then instructed to consult the hospital if they experienced decreased vision, eye pain, or any new symptoms. All patients received a loading dose of 3 consecutive monthly IVR injections (0.5 mg/0.05 mL) initially. Then, the patients were followed monthly. A single injection of IVR was repeated when the visual acuity decreased by one or more Early Treatment Diabetic Retinopathy Study lines from the last visit, or newly developed macular hemorrhage, or evidence of subretinal fluid on OCT. Primary outcome measures in this study included the change in BCVA and OCT-defined CRT at the baseline, at Months 3, 6, 9, and 12. Secondary outcome measures were the total number of injections at Month 12 and the complications of intravitreal injections.
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Statistical Analysis Visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Categorical variables were presented as numbers and percentages, whereas numerical variables were expressed as the mean and SD. The baseline characteristics and outcome measures between the groups were compared using the chi-square test for categorical variables and independent sample test or Mann–Whitney test for numerical variables. The statistical evaluation was performed using SPSS (version 16.0; SPSS Inc, Chicago, IL). A P , 0.05 was considered statistically significant. Results Ninety-six eyes of 96 patients met the inclusion criteria for the study. The mean age of the patients was 73.9 ± 8.9 years (range, 59–86 years). Forty-two patients (43.7%) were women and 54 patients (56.3%) were men. The CNV was located subfoveally in all of the patients; 74 patients (77.1%) had occult/ minimally classic CNV, and 22 patients (22.9%) had predominantly classic CNV. The greatest lesion diameter of the lesion was ,1 disk diameter in 57 patients (59.4%) and between 1 disk diameter and 2 disk diameters in 39 patients (40.6%). The overall mean number of injections was 4.4 + 1.2 (range, 3–7). Fifty-six patients (58.3%) were phakic, and 40 patients (41.7%) were pseudophakic. The general characteristics of the groups were similar (Table 1). The overall mean baseline BCVA in Snellen equivalent was 0.56 ± 0.09. Mean BCVA in Snellen equivalent at Months 3, 6, 9, and 12 were 0.63 ± 0.14, 0.61 ± 0.18, 0.59 ± 0.19, and 0.60 ± 0.18, respectively (Table 2). There was a significant difference between the mean BCVA at baseline and Month 3 (P , 0.0001); however, there was not a significant difference between the mean BCVA at baseline and Months 6, 9, and 12 (P = 0.44, P = 0.74, and P = 0.67; respectively). The mean BCVA of the phakic patients at baseline, at Months 3, 6, 9, and 12 in Snellen equivalent was
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0.56 ± 0.09 (range, 0.5–0.8), 0.64 ± 0.15 (range, 0.5– 1.0), 0.62 ± 0.21 (range, 0.1–1.0), 0.60 ± 0.22 (range, 0.1–1.0), and 0.61 ± 0.20 (range, 0.1–1.0), respectively. The mean BCVA of the pseudophakic patients at baseline, at Months 3, 6, 9, and 12 in Snellen equivalent was 0.55 ± 0.07 (range, 0.5–0.8), 0.63 ± 0.14 (range, 0.3–1.0), 0.59 ± 0.13 (range, 0.25–0.8), 0.58 ± 0.14 (range, 0.3–1.0), and 0.59 ± 0.13 (range, 0.3– 1.0), respectively (Figure 1). There was not a significant difference between the mean BCVA levels of the 2 groups at the study visits (P = 0.8, P = 0.5, P = 0.6, P = 0.4, and P = 0.7, respectively). In addition, the change in mean BCVA from the baseline to Months 3, 6, 9, and 12 was not statistically different between the 2 groups (P = 0.5, P = 0.6, P = 0.4, and P = 0.4, respectively). At Month 12, 4 of the patients (7.1%) in the pseudophakic group and 1 patient (2.5%) in the pseudophakic group had visual acuity loss $3 lines (P = 0.31). Fifty-two of the patients (92.8%) in the phakic group and 39 of the patients (97.5%) in the pseudophakic group had stable or improved vision (loss of ,3 line, or remained stable, or gained $1 lines). Twenty-seven of the patients (48.2%) in the phakic group and 12 of the patients (30.0%) in the pseudophakic group gained visual acuity $1 line (P = 0.07). Four of the patients (7.1%) in the pseudophakic group versus none of the patients in the pseudophakic group gained visual acuity $3 lines (P = 0.09). The overall mean CRT was 290 ± 81 mm (range, 148–518 mm) at the baseline, 224 ± 70 mm (range, 133–487 mm) at Month 3, 226 ± 68 mm (range, 121– 552 mm) at Month 6, 229 ± 67 mm (range, 130–487 mm) at Month 9, and 231 ± 71 mm (range, 134–537 mm) at Month 12 (Table 2). The mean CRT at Months 3, 6, 9, and 12 were statistically different from the baseline (P , 0.001, P , 0.001, P , 0.001, and P , 0.001, respectively). The mean CRT of the phakic group was 283 ± 70 mm (range, 159–441 mm) at the baseline, 213 ± 45 mm (range, 156–346 mm) at Month 3, 223 ± 72 mm (range, 121–552 mm) at Month 6, 227 ± 69 mm (range,
Table 1. General Characteristics of the Phakic and Pseudophakic Patients
Mean age Gender (female/male) Laterality (OD/OS) CNV type (O/C) GLD (,1 DD/1–2 DD) Baseline Snellen BCVA
Phakic Group
Pseudophakic Group
P
73.0 ± 5.4 years (range, 61–85 years) 25/31 26/30 45/11 36/20 0.56 ± 0.09
75.2 ± 7.6 years (range, 59–86 years) 17/23 18/22 29/11 21/19 0.55 ± 0.07
0.12 0.7 0.89 0.36 0.24 0.8
O, occult; C, classic; GLD, greatest linear dimension; DD, disk diameter.
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Month 3
Month 6
Month 9
Month 12
BCVA (Snellen) 0.56 ± 0.09 0.63 ± 0.14 0.61 ± 0.18 0.59 ± 0.19 0.60 ± 0.18 (range, 0.5–0.8) (range, 0.3–1.0) (range, 0.3–1.0) (range, 0.3–1.0) (range, 0.3–1.0) CRT (mm) 290 ± 81 224 ± 70 226 ± 68 229 ± 67 231 ± 71 (range, 148–518) (range, 133–487) (range, 121–552) (range, 130–487) (range, 134–537)
144–487 mm) at Month 9, and 235 ± 78 mm (range, 141–537 mm) at Month 12. The mean CRT of the pseudophakic group was 300 ± 94 mm (range, 148– 518 mm) at the baseline, 239 ± 92 mm (range, 133– 487 mm) at Month 3, 232 ± 63 mm (range, 139–413 mm) at Month 6, 232 ± 65 mm (range, 130–430 mm) at Month 9, and 225 ± 61 mm (range, 134–407 mm) at Month 12 (Figure 2). There was not a significant difference between the mean CRT levels of the 2 groups at the study visits (P = 0.3, P = 0.1, P = 0.5, P = 0.7, and P = 0.4, respectively). In addition, the change in mean CRT from the baseline to Months 3, 6, 9, and 12 was not statistically different between the 2 groups (P = 0.5, P = 0.4, P = 0.8, and P = 0.4, respectively). The mean baseline IOP of the phakic and pseudophakic groups were 15.5 ± 1.9 mmHg (range, 11–19 mmHg) and 15.0 ± 1.9 mmHg (range, 12–19 mmHg), respectively (P = 0.17). The mean IOP at Month 12 was 16.1 ± 2.0 mmHg (range, 13–20 mmHg) in the phakic group and 15.6 ± 1.8 mmHg (range, 12–19 mmHg) in the pseudophakic group (P = 0.3). The difference of mean IOP from the baseline to Month 12 was statistically different in the phakic group (P = 0.01), but it was not statistically different in the pseudophakic group (P = 0.06). The total number of injections at Month 12 was 4.5 ± 1.2 (range, 3–7) in the phakic group and
Fig. 1. The changes in mean visual acuity in phakic and pseudophakic patients. The graph shows the mean Snellen visual acuity levels from the baseline to Month 12. The mean visual acuity levels were not statistically different between the two groups at different time points.
4.3 ± 1.3 (range, 3–6) in the pseudophakic group; the difference between the 2 groups was not statistically significant (P = 0.5). After a total of 425 injections, no serious complications like endophthalmitis, vitreous hemorrhage, and retinal detachment were observed in any of the patients. Only mild complications like punctuate keratitis, subconjunctival hemorrhage, and transient mild anterior uveitis were detected (Table 3).
Discussion Hereditary factors, environmental factors like photochemical retinal light damage, and ocular factors like age-related alterations of the retina, inflammatory reactions, and the effect of free radicals are reported to be responsible for the pathogenesis of AMD.25 Some animal experiments showed that excessive levels of white-light exposure may induce the apoptosis of the photoreceptor cells.26,27 Therefore, the effect of cataract extraction on the progression of AMD is widely evaluated in many studies.25,28–34 In most of the studies, it was suggested that cataract surgery may increase the development and progression to advanced AMD.28–33 This phenomenon was attributed to increased light toxicity, increased inflammation, and
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Fig. 2. The changes in mean CRT in phakic and pseudophakic patients. The graph shows the mean CRT levels from the baseline to Month 12. The mean CRT levels were not statistically different between the two groups at different time points.
postoperative cystoid macular edema after cataract surgery.25 However, the theory about the cataract surgery and progression of AMD is still controversial.34 Although the effect of cataract surgery on the progression of AMD is widely studied, there are only a few studies that compare the efficacy of intravitreal anti-VEGF agents between phakic and pseudophakic patients.23,24 In a study by Baek et al,24 intravitreal ranibizumab injections on an as-needed treatment regimen were found to be effective in both phakic and pseudophakic patients. In that study, it was reported that, after a mean follow-up period of 18 months, the BCVA improved from 0.88 logMAR to 0.75 logMAR in the phakic patients and 0.86 logMAR to 0.74 logMAR in the pseudophakic patients, and the differences at the baseline and at the last follow-up visit were reported not to be significant between the 2 groups. The mean baseline CRT was reported to be 561 mm in the phakic patients and 559 mm in the pseudophakic patients, and the decrease in the mean CRT levels at Months 6, 9, and 12, and the last follow-up was not found to be statistically different between the phakic and pseudophakic patients. The mean injection number of the phakic and pseudophakic group was not different between the 2 groups, and was reported to be 3.87 and 3.62, respectively. Also, the possible Table 3. Complications in the two Groups Complications Punctate keratitis Subconjunctival hemorrhage Transient anterior uveitis
Phakic Group (%)
Pseudophakic Group (%)
P
6 (10.5) 5 (8.7)
6 (15.0) 3 (7.5)
0.2 0.7
2 (3.5)
2 (5)
0.6
effect of posterior vitreous detachment on the intravitreal ranibizumab treatment was mentioned. But, this relationship was not evaluated in the study, and it is announced that the authors were evaluating this relationship in an ongoing study.24 The anatomical outcomes for our study is similar to the study by Baek et al. However, the visual outcomes are different because of the baseline visual acuity threshold in our study. As mentioned in most of the other studies that evaluated nAMD patients with a baseline good visual acuity,16–21 usually, the overall mean visual acuity remains stable with intravitreal anti-VEGF treatments. In addition, the mean injection numbers of the study are very low in the study by Baek et al. This may be because of one of the retreatment criteria of this study, which is visual loss. At the present time, only one line of visual acuity loss is considered as a retreatment criterion, however, in the study by Baek et al, the visual acuity criterion for retreatment was considered as loss of two or more lines. In a metaanalysis of individual patient data from the ANCHOR and MARINA studies, the outcomes of monthly ranibizumab treatment was compared between the phakic and pseudophakic patients.23 In the study, 243 phakic and 179 pseudophakic eyes from the ANCHOR study and 385 phakic and 330 pseudophakic eyes from the MARINA study were evaluated. No functional or anatomical differences were found between the phakic and pseudophakic eyes in the study.23 Our overall visual and anatomical results are in concordance with the other studies that evaluated the efficacy of intravitreal anti-VEGF drugs in patients of nAMD with good baseline visual acuity. Takahashi et al,16 Axer-Siegel et al,17 Saito et al,18 Baba et al,19 Monés et al,20 Raja et al,21 and Williams and Blyth,22 reported similar results in nAMD patients with a good
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baseline visual acuity, with as-needed ranibizumab or bevacizumab treatment. However, the efficacy of the intravitreal anti-VEGF therapy was not compared between the phakic and pseudophakic patients in any of these studies.16–22 Only the number of the phakic and pseudophakic patients are mentioned in the study by Axer-Siegel et al.17 To the best of our knowledge, this is the first study that compares the efficacy of intravitreal ranibizumab between phakic and pseudophakic nAMD patients with good baseline visual acuity (0.5 Snellen equivalent or better). In this study, intravitreal ranibizumab on as-needed treatment regimen was found to be effective in both phakic and pseudophakic group patients. There was not a statistically significant difference in improvement of BCVA and CRT and the mean injection numbers between the two groups. These results may show that the therapeutic effect of intravitreal ranibizumab treatment does not change after cataract extraction in this subgroup of patients, and both phakic and pseudophakic patients may equally benefit from this therapy. In addition, there was a significant IOP increase in phakic patients after 12 months of follow-up; however, the mean IOP change was not statistically significant in pseudophakic patients. This may indicate that the phakic patients are more prone to have changes in IOP, when compared with pseudophakic patients. The main limitation of the study was the retrospective design. We used a time-domain OCT device and the incidence of posterior vitreous detachment was not evaluated in the patients. The powerful sides of this study are the homogeneity of the patients; patients with polypoidal choroidal vasculopathy and retinal angiomatous proliferation excluded, and we defined a visual acuity threshold for the patients. In addition, the baseline characteristics like the mean age, the greatest lesion diameter, and the type of the CNVs were similar in both of the two groups. Randomized controlled studies including the other variables like presence of posterior vitreous detachment, the factors that may affect the final visual outcomes would be necessary in this subgroup of patients. In conclusion, although it is thought that cataract surgery has an unfavorable effect on AMD progression, and affects the vitreous in many aspects, no difference was found in the efficacy of intravitreal ranibizumab between the phakic and pseudophakic group of the nAMD patients with good baseline visual acuity. Key words: age-related macular degeneration, cataract, lens, pseudophakia, ranibizumab, visual acuity. Author contributions: Design and conduct of the study: A. Ozkaya, Z. Alkin, and A. T. Yazici. Preparation
and review of the study: A. Ozkaya, Z. Alkin, and A. Demirok. Data collection: A. Ozkaya. Statistical analysis: Z. Alkin. References 1. Soubrane G, Coscas G, Français C, Koenig F. Occult subretinal new vessels in age-related macular degeneration. Natural history and early laser treatment. Ophthalmology 1990;97: 649–657. 2. Ferris FL III, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984;102:1640–1642. 3. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1991;109:1220–1231. 4. Singerman LJ, Kalski RS. Tunable dye laser photocoagulation for choroidal neovascularization complicating age-related macular degeneration. Retina 1989;9:247–257. 5. Akduman L, Karavellas MP, MacDonald JC, et al. Macular translocation with retinotomy and retinal rotation for exudative age-related macular degeneration. Retina 1999;19:418–423. 6. Tornambe PE, Poliner LS, Hovey LJ, Taren D. Scatter macular photocoagulation for subfoveal neovascular membranes in agerelated macular degeneration. A pilot study. Retina 1992;12: 305–314. 7. Connor TB Jr, Wolf MD, Arrindell EL, Mieler WF. Surgical removal of an extrafoveal fibrotic choroidal neovascular membrane with foveal serous detachment in age-related macular degeneration. Retina 1994;14:125–129. 8. Rubin GS, Bressler NM; Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Effects of verteporfin therapy on contrast on sensitivity: results from the treatment of age-related macular degeneration with photodynamic therapy (TAP) investigation-TAP report No 4. Retina 2002;22:536–544. 9. Margherio RR, Margherio AR, DeSantis ME. Laser treatments with verteporfin therapy and its potential impact on retinal practices. Retina 2000;20:325–330. 10. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006;26:383–390. 11. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular agerelated macular degeneration. N Engl J Med 2006;355:1432– 1444. 12. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 13. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58. 14. Schmidt-Erfurth U, Eldem B, Guymer R, et al; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 2011;118: 831–839. 15. Martin DF, Maguire MG, Ying GS, et al; CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011:364; 1897–1908.
RANIBIZUMAB IN NAMD WITH GOOD VISION OZKAYA ET AL 16. Takahashi M, Sato T, Kishi S. Intravitreal bevacizumab for age-related macular degeneration with good visual acuity. Jpn J Ophthalmol 2010;54:565–570. 17. Axer-Siegel R, Bor E, Bourla DH, et al. Intravitreal bevacizumab treatment for exudative age-related macular degeneration with good visual acuity. Retina 2012;32:1811–1820. 18. Saito M, Lida T, Kano M. Intravitreal ranibizumab for exudative age-related macular degeneration with good baseline visual acuity. Retina 2012;32:1250–1259. 19. Baba T, Kitahashi M, Kubota-Taniai M, et al. Two-year course of subfoveal pigment epithelial detachment in eyes with agerelated macular degeneration and visual acuity better than 20/40. Ophthalmologica 2012;228:102–109. 20. Monés J, Biarnés M, Trindade F, Casaroli-Marano R. FUSION regimen: ranibizumab in treatment-naïve patients with exudative age-related macular degeneration and relatively good baseline visual acuity. Graefes Arch Clin Exp Ophthalmol 2012;250: 1737–1744. 21. Raja MS, Saldana M, Goldsmith C, Burton BJ. Ranibizumab treatment for neovascular age-related macular degeneration in patients with good baseline visual acuity (better than 6/12): 12-month outcomes. Br J Ophthalmol 2010;94:1543–1545. 22. Williams TA, Blyth CP. Outcome of ranibizumab treatment in neovascular age related macular degeneration in eyes with baseline visual acuity better than 6/12. Eye (Lond) 2011;25: 1617–1621. 23. Weinberg DV, Shapiro H, Ehrlich JS. Ranibizumab treatment outcomes in phakic versus pseudophakic eyes: an individual patient data analysis of 2 phase 3 trials. Ophthalmology 2013; 12:1278–1282. 24. Baek JS, Cho HJ, Cho SW, et al. Intravitreal ranibizumab injection for neovascular age-related macular degeneration in phakic versus pseudophakic eyes. Retina 2013;33:467–473.
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25. Algvere PV, Marshall J, Seregard S. Age-related maculopathy and the impact of blue light hazard. Acta Ophthalmol Scand 2006;84:4–15. 26. Hafezi F, Marti A, Munz K, Remé CE. Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res 1997;64:963–970. 27. Grimm C, Reme CE, Rol PO, Williams TP. Blue light’s effects on rhodopsin: photoreversal of bleaching in living rat eyes. Invest Ophthalmol Vis Sci 2000;41:3984–3990. 28. Pollack A, Marcovich A, Bukelman A, Oliver M. Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation. Ophthalmology 1996;103: 1546–1554. 29. Klein R, Klein BE, Jensen SC, Cruickshanks KJ. The relationship of ocular factors to the incidence and progression of agerelated maculopathy. Arch Ophthalmol 1998;116:506–513. 30. Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 2002;109:1092–1097. 31. Wang JJ, Klein R, Smith W, et al. Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: pooled findings from the Beaver Dam and Blue Mountains eye studies. Ophthalmology 2003;110:1960–1967. 32. van der Schaft TL, Mooy CM, de Bruijn WC, et al. Increased prevalence of disciform macular degeneration after cataract extraction with implantation of an intraocular lens. Br J Ophthalmol 1994;78:441–445. 33. Smith BT, Belani S, Ho AC. Light energy, cataract surgery, and progression of age-related macular degeneration. Curr Opin Ophthalmol 2005;16:166–169. 34. Wang JJ, Fong CS, Rochtchina E, et al. Risk of age-related macular degeneration 3 years after cataract surgery: paired eye comparisons. Ophthalmology 2012;119:2298–2303.
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eovascular age-related macular degeneration (nAMD) is a major cause of visual loss among the elderly population in developed countries.1,2 Before the introduction of intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy for
nAMD, only prevention for visual loss might have been achieved in a limited number of patients with different treatment options like laser photocoagulation, vitreoretinal surgery, and photodynamic therapy.3–9 The introduction of bevacizumab (full-length antibody against VEGF-A) and ranibizumab (Fab part of antibody against VEGF-A) have led to the prevention of the visual acuity loss in most of the patients.10,11 The pivotal multicenter studies like MARINA, ANCHOR, PRONTO, EXCITE, and CATT showed that ranibizumab is effective to prevent visual acuity loss in up to 95% of the patients and is effective to
From the *Beyoglu Eye Training and Research Hospital, Istanbul, Turkey; and †Department of Ophthalmology, Medeniyet University, Istanbul, Turkey. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Abdullah Ozkaya, MD, Beyoglu Eye Training and Research Hospital, Bereketzade Camii Sok, 34421 Istanbul, Turkey; e-mail: [email protected]
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make an improvement in the visual acuity in up to 40% of the patients.11–15 However, these large studies did not include the patients with a Snellen visual acuity of 0.5 or better. Lately, some studies about the efficacy of ranibizumab treatment on an as-needed regimen were reported in this group of patients.16–22 However, except one of them,19 these studies were mainly focused on visual and anatomical results. In addition, there are only two studies to date regarding the association between IVR injection and lens status.23,24 One of these studies is a metaanalysis of the patient data from ANCHOR and MARINA studies, so this study included the nAMD patients with visual acuity between 20/320 and 20/4023, and the other study did not have a visual acuity threshold criterion.24 To the best of our knowledge, there are no reports regarding the association between lens status and efficacy of IVR in nAMD patients with a good baseline visual acuity. In this study, we aimed to compare the efficacy of IVR on an as-needed regimen between phakic and pseudophakic nAMD patients with a Snellen visual acuity $0.5. Methods In this retrospective interventional comparative study, we reviewed the records of the nAMD patients who had a baseline Snellen visual acuity $0.5 and treated with intravitreal ranibizumab injection on an as-needed treatment regimen between January 2010 and January 2011. A written informed consent for the intravitreal injections was obtained from all patients before the treatment, and the study adhered to the tenets of the Declaration of Helsinki. To be included in the study, each patient was required to have all the following criteria: age $50 years, a best-corrected Snellen visual acuity (BCVA) $0.5, to be newly diagnosed as nAMD and treatment naive, and a minimum follow-up time of 12 months. Patients were not included in the study if they had a retinal disease other than nAMD (e.g., diabetic retinopathy, retinal vein occlusion) or if they had received previous intravitreal injection therapy, or photodynamic therapy for nAMD, or if they had been diagnosed as polypoidal choroidal vasculopathy, or retinal angiomatous proliferation. Also, the phakic patients who needed cataract surgery during the follow-up time and underwent cataract surgery were excluded from the study. The patients were divided into two groups according to their lens state, which were phakic and pseudophakic groups when the patients were initially diagnosed as nAMD. The pseudophakic patients who were
included in the study were chosen among the patients who had undergone uneventful phacoemulsification surgery before the study and had intact posterior capsules. Data collected from the patients’ records included age, gender, choroidal neovascularization (CNV) type (predominantly classic or minimal classic/occult), greatest lesion diameter of CNV, BCVA, and central retinal thickness (CRT) at the baseline, at Months 3, 6, 9, and 12. Reinjection numbers at Month 12 were also recorded. All patients underwent a standardized examination including measurement of BCVA through the Early Treatment Diabetic Retinopathy Study chart at 4 m, slit-lamp biomicroscopy, measurement of intraocular pressure (IOP) through applanation tonometry, and biomicroscopic fundus examination. Fundus photography, fluorescein angiography (HRA-2; Heidelberg Engineering, Heidelberg, Germany), and optical coherence tomography (OCT) (Stratus OCT; Carl Zeiss Meditec Inc, Dublin, CA) were performed before treatment. All examinations were repeated monthly, except fluorescein angiography. Fluorescein angiography was repeated only when the cause of visual acuity deterioration could not be clarified with the other methods. Optical coherence tomography was used for detecting subretinal fluid and measurement of CRT. Central retinal thickness, defined as the mean thickness of the neurosensory retina in a central 1-mm-diameter area, was computed using OCT mapping software generated by the device. All injections were performed under sterile conditions after topical anesthesia and 10% povidone–iodine (Betadine; Purdue Pharma, Stamford, CT) scrub was used on the lids and lashes, and 5% povidone–iodine was administered on the conjunctival sac. Intravitreal ranibizumab was injected through the pars plana at 3.5 mm to 4 mm to the limbus with a 27-gauge needle. Patients were then instructed to consult the hospital if they experienced decreased vision, eye pain, or any new symptoms. All patients received a loading dose of 3 consecutive monthly IVR injections (0.5 mg/0.05 mL) initially. Then, the patients were followed monthly. A single injection of IVR was repeated when the visual acuity decreased by one or more Early Treatment Diabetic Retinopathy Study lines from the last visit, or newly developed macular hemorrhage, or evidence of subretinal fluid on OCT. Primary outcome measures in this study included the change in BCVA and OCT-defined CRT at the baseline, at Months 3, 6, 9, and 12. Secondary outcome measures were the total number of injections at Month 12 and the complications of intravitreal injections.
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Statistical Analysis Visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Categorical variables were presented as numbers and percentages, whereas numerical variables were expressed as the mean and SD. The baseline characteristics and outcome measures between the groups were compared using the chi-square test for categorical variables and independent sample test or Mann–Whitney test for numerical variables. The statistical evaluation was performed using SPSS (version 16.0; SPSS Inc, Chicago, IL). A P , 0.05 was considered statistically significant. Results Ninety-six eyes of 96 patients met the inclusion criteria for the study. The mean age of the patients was 73.9 ± 8.9 years (range, 59–86 years). Forty-two patients (43.7%) were women and 54 patients (56.3%) were men. The CNV was located subfoveally in all of the patients; 74 patients (77.1%) had occult/ minimally classic CNV, and 22 patients (22.9%) had predominantly classic CNV. The greatest lesion diameter of the lesion was ,1 disk diameter in 57 patients (59.4%) and between 1 disk diameter and 2 disk diameters in 39 patients (40.6%). The overall mean number of injections was 4.4 + 1.2 (range, 3–7). Fifty-six patients (58.3%) were phakic, and 40 patients (41.7%) were pseudophakic. The general characteristics of the groups were similar (Table 1). The overall mean baseline BCVA in Snellen equivalent was 0.56 ± 0.09. Mean BCVA in Snellen equivalent at Months 3, 6, 9, and 12 were 0.63 ± 0.14, 0.61 ± 0.18, 0.59 ± 0.19, and 0.60 ± 0.18, respectively (Table 2). There was a significant difference between the mean BCVA at baseline and Month 3 (P , 0.0001); however, there was not a significant difference between the mean BCVA at baseline and Months 6, 9, and 12 (P = 0.44, P = 0.74, and P = 0.67; respectively). The mean BCVA of the phakic patients at baseline, at Months 3, 6, 9, and 12 in Snellen equivalent was
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0.56 ± 0.09 (range, 0.5–0.8), 0.64 ± 0.15 (range, 0.5– 1.0), 0.62 ± 0.21 (range, 0.1–1.0), 0.60 ± 0.22 (range, 0.1–1.0), and 0.61 ± 0.20 (range, 0.1–1.0), respectively. The mean BCVA of the pseudophakic patients at baseline, at Months 3, 6, 9, and 12 in Snellen equivalent was 0.55 ± 0.07 (range, 0.5–0.8), 0.63 ± 0.14 (range, 0.3–1.0), 0.59 ± 0.13 (range, 0.25–0.8), 0.58 ± 0.14 (range, 0.3–1.0), and 0.59 ± 0.13 (range, 0.3– 1.0), respectively (Figure 1). There was not a significant difference between the mean BCVA levels of the 2 groups at the study visits (P = 0.8, P = 0.5, P = 0.6, P = 0.4, and P = 0.7, respectively). In addition, the change in mean BCVA from the baseline to Months 3, 6, 9, and 12 was not statistically different between the 2 groups (P = 0.5, P = 0.6, P = 0.4, and P = 0.4, respectively). At Month 12, 4 of the patients (7.1%) in the pseudophakic group and 1 patient (2.5%) in the pseudophakic group had visual acuity loss $3 lines (P = 0.31). Fifty-two of the patients (92.8%) in the phakic group and 39 of the patients (97.5%) in the pseudophakic group had stable or improved vision (loss of ,3 line, or remained stable, or gained $1 lines). Twenty-seven of the patients (48.2%) in the phakic group and 12 of the patients (30.0%) in the pseudophakic group gained visual acuity $1 line (P = 0.07). Four of the patients (7.1%) in the pseudophakic group versus none of the patients in the pseudophakic group gained visual acuity $3 lines (P = 0.09). The overall mean CRT was 290 ± 81 mm (range, 148–518 mm) at the baseline, 224 ± 70 mm (range, 133–487 mm) at Month 3, 226 ± 68 mm (range, 121– 552 mm) at Month 6, 229 ± 67 mm (range, 130–487 mm) at Month 9, and 231 ± 71 mm (range, 134–537 mm) at Month 12 (Table 2). The mean CRT at Months 3, 6, 9, and 12 were statistically different from the baseline (P , 0.001, P , 0.001, P , 0.001, and P , 0.001, respectively). The mean CRT of the phakic group was 283 ± 70 mm (range, 159–441 mm) at the baseline, 213 ± 45 mm (range, 156–346 mm) at Month 3, 223 ± 72 mm (range, 121–552 mm) at Month 6, 227 ± 69 mm (range,
Table 1. General Characteristics of the Phakic and Pseudophakic Patients
Mean age Gender (female/male) Laterality (OD/OS) CNV type (O/C) GLD (,1 DD/1–2 DD) Baseline Snellen BCVA
Phakic Group
Pseudophakic Group
P
73.0 ± 5.4 years (range, 61–85 years) 25/31 26/30 45/11 36/20 0.56 ± 0.09
75.2 ± 7.6 years (range, 59–86 years) 17/23 18/22 29/11 21/19 0.55 ± 0.07
0.12 0.7 0.89 0.36 0.24 0.8
O, occult; C, classic; GLD, greatest linear dimension; DD, disk diameter.
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 5 Table 2. The Overall Mean Visual Acuity and CRT at Different Time Points Baseline
Month 3
Month 6
Month 9
Month 12
BCVA (Snellen) 0.56 ± 0.09 0.63 ± 0.14 0.61 ± 0.18 0.59 ± 0.19 0.60 ± 0.18 (range, 0.5–0.8) (range, 0.3–1.0) (range, 0.3–1.0) (range, 0.3–1.0) (range, 0.3–1.0) CRT (mm) 290 ± 81 224 ± 70 226 ± 68 229 ± 67 231 ± 71 (range, 148–518) (range, 133–487) (range, 121–552) (range, 130–487) (range, 134–537)
144–487 mm) at Month 9, and 235 ± 78 mm (range, 141–537 mm) at Month 12. The mean CRT of the pseudophakic group was 300 ± 94 mm (range, 148– 518 mm) at the baseline, 239 ± 92 mm (range, 133– 487 mm) at Month 3, 232 ± 63 mm (range, 139–413 mm) at Month 6, 232 ± 65 mm (range, 130–430 mm) at Month 9, and 225 ± 61 mm (range, 134–407 mm) at Month 12 (Figure 2). There was not a significant difference between the mean CRT levels of the 2 groups at the study visits (P = 0.3, P = 0.1, P = 0.5, P = 0.7, and P = 0.4, respectively). In addition, the change in mean CRT from the baseline to Months 3, 6, 9, and 12 was not statistically different between the 2 groups (P = 0.5, P = 0.4, P = 0.8, and P = 0.4, respectively). The mean baseline IOP of the phakic and pseudophakic groups were 15.5 ± 1.9 mmHg (range, 11–19 mmHg) and 15.0 ± 1.9 mmHg (range, 12–19 mmHg), respectively (P = 0.17). The mean IOP at Month 12 was 16.1 ± 2.0 mmHg (range, 13–20 mmHg) in the phakic group and 15.6 ± 1.8 mmHg (range, 12–19 mmHg) in the pseudophakic group (P = 0.3). The difference of mean IOP from the baseline to Month 12 was statistically different in the phakic group (P = 0.01), but it was not statistically different in the pseudophakic group (P = 0.06). The total number of injections at Month 12 was 4.5 ± 1.2 (range, 3–7) in the phakic group and
Fig. 1. The changes in mean visual acuity in phakic and pseudophakic patients. The graph shows the mean Snellen visual acuity levels from the baseline to Month 12. The mean visual acuity levels were not statistically different between the two groups at different time points.
4.3 ± 1.3 (range, 3–6) in the pseudophakic group; the difference between the 2 groups was not statistically significant (P = 0.5). After a total of 425 injections, no serious complications like endophthalmitis, vitreous hemorrhage, and retinal detachment were observed in any of the patients. Only mild complications like punctuate keratitis, subconjunctival hemorrhage, and transient mild anterior uveitis were detected (Table 3).
Discussion Hereditary factors, environmental factors like photochemical retinal light damage, and ocular factors like age-related alterations of the retina, inflammatory reactions, and the effect of free radicals are reported to be responsible for the pathogenesis of AMD.25 Some animal experiments showed that excessive levels of white-light exposure may induce the apoptosis of the photoreceptor cells.26,27 Therefore, the effect of cataract extraction on the progression of AMD is widely evaluated in many studies.25,28–34 In most of the studies, it was suggested that cataract surgery may increase the development and progression to advanced AMD.28–33 This phenomenon was attributed to increased light toxicity, increased inflammation, and
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Fig. 2. The changes in mean CRT in phakic and pseudophakic patients. The graph shows the mean CRT levels from the baseline to Month 12. The mean CRT levels were not statistically different between the two groups at different time points.
postoperative cystoid macular edema after cataract surgery.25 However, the theory about the cataract surgery and progression of AMD is still controversial.34 Although the effect of cataract surgery on the progression of AMD is widely studied, there are only a few studies that compare the efficacy of intravitreal anti-VEGF agents between phakic and pseudophakic patients.23,24 In a study by Baek et al,24 intravitreal ranibizumab injections on an as-needed treatment regimen were found to be effective in both phakic and pseudophakic patients. In that study, it was reported that, after a mean follow-up period of 18 months, the BCVA improved from 0.88 logMAR to 0.75 logMAR in the phakic patients and 0.86 logMAR to 0.74 logMAR in the pseudophakic patients, and the differences at the baseline and at the last follow-up visit were reported not to be significant between the 2 groups. The mean baseline CRT was reported to be 561 mm in the phakic patients and 559 mm in the pseudophakic patients, and the decrease in the mean CRT levels at Months 6, 9, and 12, and the last follow-up was not found to be statistically different between the phakic and pseudophakic patients. The mean injection number of the phakic and pseudophakic group was not different between the 2 groups, and was reported to be 3.87 and 3.62, respectively. Also, the possible Table 3. Complications in the two Groups Complications Punctate keratitis Subconjunctival hemorrhage Transient anterior uveitis
Phakic Group (%)
Pseudophakic Group (%)
P
6 (10.5) 5 (8.7)
6 (15.0) 3 (7.5)
0.2 0.7
2 (3.5)
2 (5)
0.6
effect of posterior vitreous detachment on the intravitreal ranibizumab treatment was mentioned. But, this relationship was not evaluated in the study, and it is announced that the authors were evaluating this relationship in an ongoing study.24 The anatomical outcomes for our study is similar to the study by Baek et al. However, the visual outcomes are different because of the baseline visual acuity threshold in our study. As mentioned in most of the other studies that evaluated nAMD patients with a baseline good visual acuity,16–21 usually, the overall mean visual acuity remains stable with intravitreal anti-VEGF treatments. In addition, the mean injection numbers of the study are very low in the study by Baek et al. This may be because of one of the retreatment criteria of this study, which is visual loss. At the present time, only one line of visual acuity loss is considered as a retreatment criterion, however, in the study by Baek et al, the visual acuity criterion for retreatment was considered as loss of two or more lines. In a metaanalysis of individual patient data from the ANCHOR and MARINA studies, the outcomes of monthly ranibizumab treatment was compared between the phakic and pseudophakic patients.23 In the study, 243 phakic and 179 pseudophakic eyes from the ANCHOR study and 385 phakic and 330 pseudophakic eyes from the MARINA study were evaluated. No functional or anatomical differences were found between the phakic and pseudophakic eyes in the study.23 Our overall visual and anatomical results are in concordance with the other studies that evaluated the efficacy of intravitreal anti-VEGF drugs in patients of nAMD with good baseline visual acuity. Takahashi et al,16 Axer-Siegel et al,17 Saito et al,18 Baba et al,19 Monés et al,20 Raja et al,21 and Williams and Blyth,22 reported similar results in nAMD patients with a good
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baseline visual acuity, with as-needed ranibizumab or bevacizumab treatment. However, the efficacy of the intravitreal anti-VEGF therapy was not compared between the phakic and pseudophakic patients in any of these studies.16–22 Only the number of the phakic and pseudophakic patients are mentioned in the study by Axer-Siegel et al.17 To the best of our knowledge, this is the first study that compares the efficacy of intravitreal ranibizumab between phakic and pseudophakic nAMD patients with good baseline visual acuity (0.5 Snellen equivalent or better). In this study, intravitreal ranibizumab on as-needed treatment regimen was found to be effective in both phakic and pseudophakic group patients. There was not a statistically significant difference in improvement of BCVA and CRT and the mean injection numbers between the two groups. These results may show that the therapeutic effect of intravitreal ranibizumab treatment does not change after cataract extraction in this subgroup of patients, and both phakic and pseudophakic patients may equally benefit from this therapy. In addition, there was a significant IOP increase in phakic patients after 12 months of follow-up; however, the mean IOP change was not statistically significant in pseudophakic patients. This may indicate that the phakic patients are more prone to have changes in IOP, when compared with pseudophakic patients. The main limitation of the study was the retrospective design. We used a time-domain OCT device and the incidence of posterior vitreous detachment was not evaluated in the patients. The powerful sides of this study are the homogeneity of the patients; patients with polypoidal choroidal vasculopathy and retinal angiomatous proliferation excluded, and we defined a visual acuity threshold for the patients. In addition, the baseline characteristics like the mean age, the greatest lesion diameter, and the type of the CNVs were similar in both of the two groups. Randomized controlled studies including the other variables like presence of posterior vitreous detachment, the factors that may affect the final visual outcomes would be necessary in this subgroup of patients. In conclusion, although it is thought that cataract surgery has an unfavorable effect on AMD progression, and affects the vitreous in many aspects, no difference was found in the efficacy of intravitreal ranibizumab between the phakic and pseudophakic group of the nAMD patients with good baseline visual acuity. Key words: age-related macular degeneration, cataract, lens, pseudophakia, ranibizumab, visual acuity. Author contributions: Design and conduct of the study: A. Ozkaya, Z. Alkin, and A. T. Yazici. Preparation
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