Purpose
To compare the short-term efficacy and safety of intravitreal ranibizumab versus bevacizumab in treating myopic choroidal neovascularization (CNV).
Design
Prospective, comparative, randomized, interventional study.
Methods
Thirty-two eyes from 32 patients with myopic CNV were consecutively enrolled and randomly treated, in a 1:1 ratio, with intravitreal ranibizumab (0.5 mg) or bevacizumab (1.25 mg) as needed, after the first injection. ETDRS best-corrected visual acuity (BCVA), foveal center thickness (FCT) on optical coherence tomography (OCT), and fluorescein angiographic findings were examined before and after treatment. Patients were followed up for 6 months.
Results
No statistically significant difference in the BCVA improvement, as well as in the FCT reduction, was found between groups during follow-up ( P value at 1, 3, 6 months > .05). Complete resolution of fluorescein leakage was observed in all 16 bevacizumab-treated eyes and in 15 out of 16 (93.7%) ranibizumab-treated eyes. No ocular or systemic adverse effects from treatment were encountered.
Conclusion
This randomized clinical study cannot determine a statistically significant difference in anti-VEGF treatment effect between ranibizumab and bevacizumab for the treatment of CNV secondary to pathologic myopia. A larger study is required to determine the relative efficacy and duration of action of these drugs.
Choroidal neovascularization (CNV) secondary to pathologic myopia is a known cause of severe visual loss for young and middle-aged patients. Nearly 10% of patients with degenerative retinal findings consistent with high myopia develop choroidal neovascularization. Although the natural course of myopic CNV is highly variable, the long-term prognosis is known to be poor.
Treatment options include thermal laser photocoagulation, surgical removal, macular translocation, and photodynamic therapy (PDT) with or without intravitreal triamcinolone acetonide. Nevertheless, the most appropriate treatment has not yet been established. Photodynamic therapy with verteporfin is currently the only approved and most widely used treatment for subfoveal CNV in pathologic myopia that has shown stabilization of vision compared with placebo. At 1 year, 72% of treated eyes compared with 44% of placebo eyes lost fewer than 8 letters, which was the primary outcome measure. However, the 2-year outcomes of the Verteporfin in Photodynamic Therapy (VIP) trial failed to demonstrate a statistically significant benefit in the PDT-treated eyes, as 36% of the verteporfin-treated eyes and 51% of eyes in the placebo group lost at least 8 letters.
Vascular endothelial growth factor (VEGF)-A has been implicated as a major angiogenic stimulus responsible for CNV secondary to age-related macular degeneration (AMD). In 2005, Nguyen and associates reported on the use of systemic bevacizumab for the treatment of subfoveal CNV secondary to pathologic myopia. This report provided the first evidence that VEGF-A played an important part in promoting CNV in pathologic myopia.
In the past few years, a number of studies demonstrated that intravitreal anti-VEGF therapy for neovascular age-related macular degeneration, with either ranibizumab or bevacizumab, can result in both functional and anatomic improvement that appeared to be superior compared with PDT. However, it should be emphasized that whereas the benefit of ranibizumab is based on several controlled long-term and large-scale randomized trials, the experience of bevacizumab is limited to smaller, uncontrolled short-term studies. Ranibizumab (Lucentis; Genentech, San Francisco, California, USA) is a fragment of a recombinant monoclonal antibody that binds to and inhibits all the biologically active forms of VEGF-A. In June 2006, the Food and Drug Administration (FDA) approved ranibizumab, which is formulated for intravitreal injection, for the treatment of neovascular age-related macular degeneration. Bevacizumab (Avastin; Genentech, San Francisco, California, USA) is a full-length antibody that is derived from the same mouse monoclonal antibody precursor as ranibizumab, neutralizes vascular endothelial growth factor, and costs considerably less than ranibizumab when administered as an intraocular injection. In February 2004, the FDA approved bevacizumab for the intravenous treatment of metastatic cancer of the colon or rectum; therefore, intraocular administration of bevacizumab is currently entirely off-label.
The purpose of this prospective, randomized, interventional pilot study was to compare the efficacy and safety of intravitreal injection of ranibizumab versus bevacizumab in patients with myopic CNV.
Patients and Methods
From February 2008 to December 2008, 32 eyes from 32 patients with myopic CNV were consecutively enrolled in this prospective, randomized case series.
Inclusion criteria were: pathologic myopia, defined as axial length (Carl Zeiss IOLMaster V 4.07; Carl Zeiss Meditec, Dublin, California, USA) more than 26.5 mm; subfoveal or juxtafoveal CNV (CNV was classified as juxtafoveal if the lesion was closer than 200 µm but not under the geometric center of the foveal avascular zone); and evidence of leakage from CNV on fluorescein angiography (FA).
Exclusion criteria were: prior treatment for CNV, other ocular diseases that could affect the visual acuity, angioid streaks, trauma, choroiditis, hereditary diseases in the study or the fellow eye, aphakia, previous vitreoretinal surgery, prior history of bleeding diathesis, prior cerebrovascular accident, pulmonary embolus or deep venous thrombosis, myocardial infarction or uncompensated coronary artery disease within the past 6 months, major surgery within the prior 6 weeks, or ongoing uncontrolled hypertension.
Eligible patients were randomly assigned in a 1:1 ratio to intravitreal injection of ranibizumab or bevacizumab in 1 eye. If both eyes were eligible, the eye with worse VA was the study eye unless the other eye was deemed more suitable for medical reasons.
A complete ophthalmic examination was undertaken in all patients. Best-corrected visual acuity (BCVA) was measured according to a standardized refraction protocol, using the ETDRS chart at 4 meters distance by a single well-trained and experienced orthoptist, who was masked to the study. The proportions of eyes that had 10 letters (2 lines) or more and 15 letters (3 lines) or more BCVA improvement, as well as BCVA deterioration of these same amounts relative to baseline, were reported at 6-month follow-up.
Foveal center thickness (FCT) was measured for all eyes using the ocular coherence tomography (Stratus OCT, V4.01; Carl Zeiss Meditec) high-resolution Radial Lines protocol and the Retinal Thickness Map analysis program. This map was created from 6 6-mm individually and sequentially acquired high-resolution radial B-scans that intersected at the fovea. All OCT examinations at baseline and at follow-up were done by an experienced retinal specialist (F.A.). Only well-centered scans without overt algorithm failure messages were selected for analysis. Low-quality scans were reacquired. A target of signal strength equal to or greater than 7 was deemed desirable, although not always possible because of factors such as media opacity and the elongated axial lengths in eyes with pathologic myopia. FCT and its standard deviation (FCTSD) were measured automatically by the OCT software. An FCTSD-to-FCT ratio lower than 10% was deemed desirable. A greater than 10% decrease from the baseline thickness was defined as a reduction and a greater than 10% increase was defined as an increase compared to the foveal center thickness before treatment.
The leakage from the CNV was evaluated on fluorescein angiography (ImageNet; Topcon, Tokyo, Japan), performed by a trained photographer masked to the study, in the late phase (6–8 min) compared with the early phase (first 1–2 min). The leakage was compared between the times before and after treatment and was described as absent (CNV closure) or persistent. Recurrence was defined as evidence of leakage from a previously closed CNV.
All FA and OCT evaluations were interpreted by 2 retinal specialists (M.G. and G.R.) in an unmasked fashion. If there were questions regarding interpretation of the study data, other retinal specialists (F.A. and N.F.) were approached in consultation.
Intraocular pressure (IOP) and diastolic and systolic blood pressure were also recorded at baseline and during follow-up.
Ranibizumab and Bevacizumab Injection
Before injection, topical anesthesia was induced by tetracaine (1%) eyedrops. Povidone-iodine was applied to the eyelid margins and the lashes. After application of a sterile drape, a lid speculum was inserted. Povidone-iodine (5%) was applied to the conjunctiva bulbi and the fornices for at least 3 minutes. A volume of 0.05 mL (1.25 mg of bevacizumab and 0.5 mg of ranibizumab) was injected through a 30-gauge needle at 3.5 to 4 mm of inferotemporal limbus. Bevacizumab (0.1 mL) was drawn under sterile conditions from a bevacizumab infusion vial (25 mg/mL) by our pharmacy department and was not diluted further.
Follow-up visits were arranged at 4-week intervals. On each evaluation BCVA, complete ocular examination, OCT, FA, IOP, and blood pressure measurement were performed.
After the first injection, re-treatment was based on the presence of persistent leakage on FA or intraretinal or subretinal fluid on OCT. Monthly additional injections were performed in these eyes until absence of fluorescein leakage from the CNV and absence of any fluid collections on OCT were obtained.
Statistical Analysis
We used the X 2 test for categorical variables and variance analysis (ANOVA) for continuous variables to identify any difference in pretreatment populations.
The main outcome measures were changes in BCVA and FCT between baseline and month 6 follow-up visit. Data were analyzed with a 1-tailed, paired t test.
To compare treatment efficacy between the ranibizumab- and the bevacizumab-treated eyes during the 6-month follow-up period, we used the variance analysis (ANOVA) for continuous variables. ANOVA was also used to determine any difference between the groups in the number of injections delivered during the 6-month period.
Changes in IOP and diastolic and systolic blood pressure between baseline and month 6 were assessed with a 2-tailed t test.
A P value <.05 was considered significant.
Results
Patient demographics and comparisons of data at baseline are summarized in Table 1 . Thirty-two eyes from 32 patients (22 female and 10 male) were consecutively enrolled and randomly treated, in a 1:1 ratio, with intravitreal injection of ranibizumab or bevacizumab.
| Ranibizumab (16 Eyes of 16 Patients) | Bevacizumab (16 Eyes of 16 Patients) | P Value | |
|---|---|---|---|
| Age (years) | 60.63 ± 10.48 | 59.06 ± 11.42 | .69 a |
| Gender | |||
| Male | 4 | 6 | .44 b |
| Female | 12 | 10 | .44 b |
| Axial length (mm) | 29.38 ± 2.86 | 30.11 ± 2.53 | .45 a |
| BCVA (number of ETDRS letters [Snellen equivalent]) | 26.44 [20/76] ± 12.58 | 29.50 [20/66] ± 12.98 | .50 a |
| Foveal center thickness (µm) | 251 ± 64.80 | 237 ± 40.79 | .47 a |
All cases of CNV were predominantly classic in angiographic appearance. All patients completed follow-up at 6 months.
There was no significant difference in the age, gender, axial length, pretreatment visual acuity, and initial FCT between the ranibizumab and bevacizumab groups ( Table 1 ).
At baseline the mean BCVA (± SD) in the ranibizumab and bevacizumab groups was 26.44 (± 12.58) letters (Snellen equivalent: 20/76) and 29.50 (± 12.98) letters (Snellen equivalent: 20/66), respectively. Six months after treatment, both ranibizumab and bevacizumab significantly increased the BCVA to 43.75 (± 9.91) letters (Snellen equivalent: 20/33) ( P value = .000008) and 45.37 (± 9.95) letters (Snellen equivalent: 20/32) ( P value = .0000009), respectively. The mean BCVA (± SD) improvement at month 6 for the ranibizumab- and the bevacizumab-treated eyes was 17.31 (± 11.10) letters and 15.87 (± 8.41) letters, respectively ( Table 2 ). There was no statistically significant difference in the BCVA improvement achieved with these 2 agents during follow-up ( P value at 1 month = .52; P value at 3 months = .90; P value at 6 months = .68) ( Figure 1 ). At 6-month follow-up, BCVA improved 10 letters (2 lines) or more in 12 out of 16 (75%) ranibizumab-treated eyes and improved 15 letters (3 lines) or more in 9 out of 16 (56.2%) ranibizumab-treated eyes. The corresponding figures for the bevacizumab-treated group were 13 of 16 (81.2%) and 10 of 16 (62.5%), respectively. No treated eyes experienced a worsening of BCVA from baseline ( Table 3 ).
| BCVA (Mean Number of ETDRS Letters [Snellen Equivalent]) | FCT (µm) | Mean Injections | ||||
|---|---|---|---|---|---|---|
| Month 0 | Month 6 | Number of ETDRS Letters Changed at 6 Months | Month 0 | Month 6 | Number at 6 Months | |
| Ranibizumab (16 eyes) | 26.44 [20/76] ± 12.58 | 43.75 [20/33] ± 9.92 | +17.31 ± 11.10 | 251 ± 64.81 | 206 ± 52.19 | 2.81 ± 1.17 |
| Bevacizumab (16 eyes) | 29.50 [20/66] ± 12.98 | 45.37 [20/32] ± 9.95 | +15.87 ± 8.41 | 237 ± 40.79 | 185 ± 36.93 | 2.44 ± 0.89 |
| Ranibizumab Number of Treated Eyes out of 16 (%) | Bevacizumab Number of Treated Eyes out of 16 (%) | |
|---|---|---|
| BCVA changes at month 6 | ||
| Gained ≥15 letters | 9 (56.2%) | 10 (62.5%) |
| Gained ≥10 letters | 12 (75%) | 13 (81.2%) |
| Lost≥15 letters | 0 | 0 |
| Lost≥10 letters | 0 | 0 |
| FCT changes at month 6 | ||
| Decreased by 10% or more | 10 (62.5%) | 14 (87.5) |
| Equal | 4 (25%) | 2 (12.5%) |
| Increased by 10% or more | 2 (12.5%) | 0 |
| FA leakage changes at month 6 | ||
| Absence | 15 (93.7%) | 16 (100%) |
| Persistence | 1 (6.2%) | 0 |
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