Two-Year Outcome of Intravitreal Injections of Ranibizumab for Myopic Choroidal Neovascularization

Abstract

Purpose:

To evaluate the 2-year outcome, efficacy, and safety of intravitreal ranibizumab injections for myopic choroidal neovascularization (CNV).

Methods:

We retrospectively reviewed the medical records of 28 consecutive eyes that received intravitreal injections of ranibizumab for myopic CNV with a 24-month follow-up. Retreatment was performed as needed in eyes with persistent or recurrent CNV. Patient demographic data, best-corrected visual acuity (BCVA), CNV findings on fluorescent angiography, central macular thickness on optical coherence tomography, total number of treatments, and complications were recorded.

Results:

Mean baseline BCVA was 0.53±0.32 logMAR [Snellen equivalent (SE), 6/20], and improved significantly to 0.28±0.32 logMAR (SE, 6/11) at 1 year and 0.29±0.28 logMAR (SE, 6/12) at 2 years (both P<0.01, Wilcoxon signed-rank test). The average number of total injections over 2 years was 3.32 (SD 2.13). A mean of 2.82 injections were performed in the first year, and 0.50 in the second year. Twenty-three eyes (82.1%) had no need for treatment during the second year of follow-up. Mean improvement from the baseline was 2.57 Snellen lines (SD 2.35) at 1 year, and 2.29 lines (SD 2.69) at 2 years. At 2 years, 11 eyes (39.3%) showed a gain of at least 3 lines after treatment. No complications were noted after treatment.

Conclusions:

Intravitreal ranibizumab injection was safe and effective in treating myopic CNV, with visual improvement maintained over 2 years.

Introduction

To date, the only FDA-approved standard treatment for myopic choroidal neovascularization (CNV) is photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis, Basel, Switzerland). Compared with placebo, PDT with verteporfin was demonstrated more likely to stabilize vision in patients with myopic CNV at 1 year; however, the differences were not statistically significant at 2 years, and the visual improvements were limited.^1,2 In recent years, the mainstream therapy for CNV secondary to age-related macular degeneration (AMD) has shifted to intravitreal injection with anti-vascular endothelial growth factor (VEGF) drugs, mainly ranibizumab (Lucentis; Novartis).³ Recently, several clinical studies that reported using ranibizumab to treat myopic CNV also showed promising results with significant visual improvement.^4–19 Ranibizumab was then approved in European Union (EU) as the first effective anti-VEGF treatment for myopic CNV in July 2013. However, there have been few reports concerning the long-term efficacy and safety of ranibizumab for myopic CNV. In this study, we sought to evaluate the 2-year outcomes of intravitreal ranibizumab to treat CNV secondary to pathologic myopia in an Asian population.

Methods

The hospital institutional review board approved this study, following the tenets of the Declaration of Helsinki. We retrospectively reviewed the medical records of 28 consecutive eyes with CNV secondary to pathologic myopia that fulfilled the inclusion and exclusion criteria and were treated with intravitreal ranibizumab with a follow-up of 2 years during February 2008 and December 2013. The first treatment for each patient was performed between February 2008 and December 2011. The inclusion criteria included high myopia with spherical equivalent of −6 diopters or more and an axial length of 26 mm or more, active subfoveal or juxtafoveal CNV, treatment with intravitreal ranibizumab injections, and a follow-up of at least 2 years. Exclusion criteria were CNV secondary to causes other than myopic CNV (such as AMD, angioid streaks, choroiditis, or trauma), any chorioretinopathy other than pathologic myopia (including central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, vasculitis, or uveitis), and previous treatment for myopic CNV within the previous 3 months. During the study periods, the best and standard initial treatment protocols (ie, single injection or 3 monthly loading injections) for myopic CNV had not been determined. Therefore, both treatment methods were used in our study.

At baseline, every patient underwent a comprehensive ophthalmologic examination, and the following were recorded: best-corrected visual acuity (BCVA), intraocular pressure, and the results of slit lamp biomicroscopy, dilated fundus examination, fluorescent angiography (FA), and optical coherence tomography (OCT) (RTVue Scanner; Optovue, Inc., Fremont, CA). The CNV lesion was evaluated for location and composition on FA, and central macular thickness (CMT) was measured using OCT.

After obtaining written informed consent, we performed surgical procedures in an outpatient setting with topical anesthesia. Injection of 0.05 mL of ranibizumab (0.5 mg) was accomplished using a 30-gauge needle through the pars plana into the vitreous cavity.

All patients were followed 1 week after injection and then monthly thereafter for 2 years. Retreatment was done as needed with a single ranibizumab injection in eyes with persistence or recurrence of CNV, defined by a visual loss of at least 1 Snellen line, metamorphopsia, macular edema, or subretinal fluid on OCT, or CNV leakage on FA.

All patients were informed of the off-label use of ranibizumab for myopic CNV and possible adverse effects. Women of childbearing age were asked to use contraception during treatment. At monthly follow-up, examinations included BCVA, intraocular pressure, slit lamp biomicroscopy, dilated fundus examination, and OCT. FA was performed at baseline and as required.

Patient demographic data and examination results at baseline and at each visit, including BCVA, findings of FA and OCT, total number of injections, and adverse events after injections, were recorded.

BCVA was measured using Snellen charts and was converted into the logarithm of the minimum angle of resolution (logMAR) for data analysis. We used SPSS statistical software, version 12.0 (SPSS, Inc., Chicago, IL) for statistical analysis. Continuous variables were compared using Wilcoxon signed-rank test and t-test. For categorical variables, we compared the outcome by Fisher's exact test between groups. We also used binary logistic regression analysis to estimate odds ratio (OR) and their corresponding 95% confidence intervals (CIs) of potential prognostic factors for visual outcome. A P value<0.05 was regarded statistically significant.

Results

Twenty-eight eyes with active myopic CNV were included and treated with at least 1 injection of ranibizumab in this retrospective study. There were 18 women (64.3%), and the mean age of the patients was 45.07 years [standard deviation (SD) 12.64; range 22–65 years). The average spherical equivalent was −11.34 diopters (SD 3.91; range −6.00 to −19.50); the average axial length was 29.18 mm (SD 1.58; range 27.32–31.54). Only 2 eyes (7.1%) had received prior PDT treatment. All CNVs were predominantly classic in angiographic appearance. Overall, 24 eyes (85.7%) had subfoveal CNVs, while 4 (14.3%) had juxtafoveal CNVs. Thirteen eyes adopted the regimen of 3 monthly loading doses, while 15 eyes started with a single initial injection. None of the patients had systemic or ocular complications following treatment.

The average number of ranibizumab injections was 3.32 (SD 2.13; range 1–10) over 2 years. In addition to the initial treatment (ie, a single injection or 3 monthly injections), 1.39 (SD 2.27; range 0–9) additional injections were performed in the subsequent months through 2 years. Moreover, a mean of 2.82 (SD 1.39; range 1–6) injections were performed in the first year and 0.50 (SD 1.23; range 0–5) in the second year. Twenty-three eyes (82.1%) did not require treatment during the second year of follow-up. Overall, 10 eyes (35.7%) required additional 2–9 injections for retreatment after an initial single injection or 3 monthly loading doses, and 8 out of 10 (80%) eyes started with a single initial injection.

Figure 1 shows the changes in mean logMAR BCVA during the 2-year follow-up. Mean baseline BCVA was 0.53 logMAR (SD 0.32). During the 12-month follow-up, mean BCVA was 0.39 logMAR (SD 0.33) at 1 month, 0.33 logMAR (SD 0.32) at 2 months, 0.30 logMAR (SD 0.30) at 3 months, 0.26 logMAR (SD 0.26) at 6 months, 0.27 logMAR (SD 0.29) at 9 months, 0.28 logMAR (SD 0.32) at 12 months, 0.30 logMAR (SD 0.30) at 15 months, 0.28 logMAR (SD 0.30) at 18 months, 0.30 logMAR (SD 0.32) at 21 months, and 0.29 logMAR (SD 0.28) at 24 months. The differences in mean BCVA at each follow-up visit over baseline were significant (P<0.001, Wilcoxon signed-rank test). Mean BCVA improved significantly between 1 and 2 months (P=0.011) but not between 2 and 3 months (P=0.246, Wilcoxon signed-rank test).

FIG. 1.

Changes in the mean logMAR best-corrected visual acuity (BCVA) during the 2-year follow-up. The error bars illustrate 1 standard error of the mean. The mean BCVA improved from 0.53 logMAR (SD 0.32) at baseline to 0.28 logMAR (SD 0.32) at 12 months and 0.29 logMAR (SD 0.28) at 24 months. The differences in BCVA at each follow-up visit over baseline were significant (all P<0.001, Wilcoxon signed-rank test). Mean BCVA improved significantly between 1 and 2 months (P=0.011) but not between 2 and 3 months (P=0.246, Wilcoxon signed-rank test).

Mean improvement from the baseline was 2.57 Snellen lines (SD 2.35; range −1 to 7 lines) at 1 year, and 2.29 lines (SD 2.69; range −2 to 7 lines) at 2 years. At 2 years, 19 eyes (67.9%) showed a gain of at least 1 line after treatment, with 12 eyes (42.9%) improved by 2 or more lines and 11 eyes (39.3%) improved by 3 or more lines; 7 eyes (25%) remained unchanged, and another 2 eyes (7.1%) lost 1 line and 2 lines from baseline, respectively.

Figure 2 shows the changes in mean CMT on OCT after treatment. At baseline, the average CMT was 282.18 μm (SD 99.65). The mean CMT reduced gradually to 239.91 μm (SD 35.73) at 1 year and 237.59 μm (SD 40.06) at 2 years, a reduction that was statistically significant (P=0.030 and 0.033, respectively; 2-tailed t-test).

FIG. 2.

The changes in mean central macular thickness (CMT) on optical coherence tomography after treatment. The error bars illustrate 1 standard error of the mean. The mean CMT reduced gradually from 282.18 μm (SD 99.65) to 239.91 μm (SD 35.73) at 1 year and 237.59 μm (SD 40.06) at 2 years (P=0.030 and 0.033, respectively; 2-tailed t-test).

Although the total number of injections at 1 year in eyes with initial 3 monthly loading doses was significantly higher than eyes with a single initial injection [3.38 (SD 0.961) vs. 2.33 (SD 1.543); P=0.038; t-test], there were no significant differences between eyes with or without the loading doses in terms of the total injections during year 2, the total injections over 2 years, the number of reinjections required, and visual improvement.

Considering aging might influence the number of total injections and required reinjections, we sorted the eyes by patients' age into 2 groups. Among the eyes of patients older than 50 years, 5 of 11 eyes (45.5%) adopted the 3 monthly loading doses, while 8 of 15 eyes (47.1%) with the loading doses in patients younger than 50 years. There was no significant difference in initial dosing regimens between 2 groups (P=1.000). Although the mean of the numbers of total injections and required reinjections seemed higher in eyes of patients older than 50 years, there was no statistical significance [total injections: 4.00 (SD 2.828) vs. 2.88 (SD 1.453), P=0.247; reinjections: 2.09 (SD 3.015) vs. 0.94 (SD 1.560), P=0.195]. Moreover, the mean of BCVA improvement at 12 and 24 months in eyes of patients older than 50 years seemed comparable to those of patients younger than 50 years [2.27 (SD 2.149) vs. 2.76 (SD 2.513) Snellen lines at 12 months, P=0.598; 1.91 (SD 2.982) vs. 2.53 (SD 2.552) Snellen lines at 24 months, P=0.561]. There was also no statistical significance between these age groups in terms of the mean BCVA at baseline, 12, or 24 months.

Among 17 eyes with a baseline BCVA better than 6/30 (0.7 logMAR), 14 (82.4%) achieved a BCVA of 6/12 or more at 2 years; however, among eyes with baseline BCVA of 6/30 or worse, only 36.4% (4 of 11 eyes) achieved this level (P=0.02; Fisher's exact test). Binary regression analysis demonstrated that eyes with initial BCVA of 6/30 or worse were less likely to have a visual outcome of 6/12 or better at 2 years than eyes with initial BCVA better than 6/30 (OR, 0.068; 95% CI, 0.005–0.926; P=0.044). Moreover, eyes with a higher severity of myopia (per diopter of spherical equivalent) were less likely to achieve a BCVA of 6/12 or better at 2 years (OR, 0.697; 95% CI, 0.489–0.994; P=0.046).

Discussion

CNV is an important cause of visual loss in eyes with pathologic myopia, characterized by extremely elongated axial length, chorioretinal degeneration, and lacquer cracks. CNV may cause subretinal hemorrhage, exudation, fibrosis, and atrophic scars, leading to permanent visual loss.²⁰ In eyes with CNV secondary to pathologic myopia, VEGF concentrations are markedly increased when compared with the controls.²¹ The angiogenic activity of VEGF may be associated with the pathogenesis of myopic CNV.

Ranibizumab, an anti-VEGF medication, has been approved and widely used as the primary treatment for CNV secondary to AMD. Theoretically, its therapeutic effects on CNV may also be effective for CNV secondary to pathologic myopia. Previous studies using ranibizumab in treating myopic CNV showed promising results.

Silva et al., Konstantinidis et al., and Gharbiya et al. reported short-term studies of myopic CNV treated with intravitreal ranibizumab, and significant improvements were observed.^4,6,9 Other longer-term studies reported that 65% to 92.7% of eyes with myopic CNV achieved visual improvement of at least 1 line after at least 1 year of follow-up after intravitreal injections of ranibizumab.^{7,8,10–14,16,17} Our study showed that 67.9% achieved a gain of at least 1 line after treatment at 2 years. These proportions seem higher than those for eyes treated with PDT at 1 and 2 years.^1,2 A retrospective study by Yoon et al. reported that intravitreal anti-VEGF injections were superior to PDT for treating myopic CNV at 1 year.²² In July 2013, ranibizumab was first approved in EU as effective anti-VEGF treatment for myopic CNV. Recently, the Radiance study also concluded that ranibizumab treatment provided superior BCVA gains versus PDT up to 3 months.¹⁷

The vast variation in results probably comes from nonuniform study design and variety of CNV severity, baseline visual acuities, proportion of previous PDT treatment, follow-up durations, sample sizes, and different initial treatment protocols. Currently, there are few reports with a follow-up of at least 2 years. In the report of Franqueira et al., 30% of 40 eyes gained at least 15 letters (3 lines) at 2 years, but BCVA worsened in 30% of eyes at 2 years. Besides, they found that 25% of the patients only had treatments during the first year.¹⁵ Another study by Ruiz-Moreno et al.²³ reported a gain of 4.3 letters in 24 eyes treated by Lucentis at 4 years. Compared with our study, these 2 studies had much higher percentages of eyes treated by PDT previously (37.5% in Franqueira et al. study and 54% in Ruiz-Moreno et al. study).^15,23 Our study with 26 treatment-naive eyes (92.9%) showed that 39.3% of eyes improved at least 3 lines and only 2 eyes (7.1%) had worsened vision at 2 years. Our results are promising, and 82.1% of eyes had no need for treatment during the second year, indicating good maintenance of therapeutic effects over 2 years.

Another study with 15 treatment-naive eyes by Lai et al. showed that logMAR VA improved from 1.04 to 0.53 at 2 years, and 73.3% did not need additional treatment after 3 monthly loading doses.²⁴ Our study showed that mean logMAR VA of 28 eyes improved from 0.53 to 0.29 at 2 years, and 11 (74.6%) out of 13 eyes with 3 monthly loading doses did not need additional treatment during the follow-up of 2 years.

In our study, we included eyes starting with both a single injection and 3 monthly injections. In light of the potential risks of retinal break, retinal detachment, and other complications in highly myopic patients receiving intravitreal injections and the lower activity of myopic CNV than CNV secondary to AMD, some studies used 1 single initial injection followed by reinjections as needed protocol, and they also showed promising outcomes.^8,10,11 However, in our study, although the total number of injections during the first year was higher in eyes with the initial 3 monthly loading doses [3.38 (SD 0.961) injections, compared with 2.33 (SD 1.543) in eyes with a single initial injection; P=0.038], the loading doses did not affect the results in terms of the total injections during the second year, the total injections over 2 years, the number of reinjections required after initial injections, visual improvement, and rate of complications. Moreover, eyes with a single initial injection may be prone to have a higher possibility (8 out of 15 eyes) of requiring additional injections during the follow-ups over 2 years.

Regarding the prognostic factors, Franqueira et al.¹⁵ found a significant negative correlation between age and final visual acuity. Patients aged <55 years had a higher improvement in visual acuity after intravitreal injections of ranibizumab for myopic CNV. Also, Ruiz-Moreno et al.²³ noted BCVA gains were more marked in younger patients after intravitreal anti-VEGF therapy. That effect might be due to smaller CNV membranes, less chorioretinal atrophy, and age-related retinal changes, and a healthier retinal pigment epithelial layer in younger patients.¹⁵ However, Lai et al.²⁴ did not find a significant correlation between age and visual prognosis. Although our study showed that patients aged younger than 50 years tended to have slightly more visual improvement and fewer numbers of total injections and reinjections over 2 years, these results were not statistically significant.

Calvo-Gonzalez et al.¹² identified that a better baseline BCVA and a nonsubfoveal location were positive predictive factors of final BCVA for myopic CNV after intravitreal ranibizumab (mean follow-up of 15.9 months). Lai et al.²⁴ reported that eyes with higher severity of myopia were less likely to develop a visual gain of 3 or more lines at 2 years after anti-VEGF therapy. In our study predominantly of subfoveal CNVs treated with ranibizumab, we also found that an initial BCVA of 6/30 or worse and higher severity of myopia were negative predictive factors for achieving visual outcomes of 6/12 or better at 2 years. These factors are probably associated with the extent and severity of photoreceptor damage.

In conclusion, intravitreal ranibizumab injection was a safe and effective treatment for eyes with CNV secondary to pathologic myopia, and visual improvement would maintain over 2 years. However, our study had a retrospective design, a small sample size, and a lack of standardized VA testing. Further prospective trials are needed to evaluate the safety and efficacy of intravitreal ranibizumab for myopic CNV.

Footnotes

Acknowledgments

This study was supported by the Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (grant VGHKS 102-078).

Author Disclosure Statement

The authors have no conflicts of interest or relevant commercial associations to disclose. No competing financial interests exist.

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