Purpose
To explore the benefit of rapid induction with intravitreal bevacizumab for neovascular age-related macular degeneration (AMD).
Design
Single-institution prospective randomized pilot study.
Methods
Patients with treatment-naïve neovascular AMD were randomized 1:1:1 into 1 of 3 groups based on the induction sequence: (1) every 2 weeks for 3 consecutive injections; (2) every 4 weeks for 3 consecutive injections; and (3) immediate pro re nata (prn) after the first injection. Retinal angiomatous proliferation and polypoidal choroidal vasculopathy were excluded. Best-corrected visual acuity (BCVA) and central retinal thickness using optical coherence tomography (OCT) were measured at baseline and at each follow-up. After induction, bevacizumab was administered as needed based mainly on OCT. Main outcome measure was mean initial fluid-free interval after induction. Secondary outcomes were mean improvement in BCVA and central retinal thickness.
Results
Each group included 30 patients (30 eyes). Mean initial fluid-free interval was 2.4, 3.4, and 3.5 months for biweekly induction, monthly induction, and immediate prn groups, respectively ( P = .03). Significance was lost when corrected for age and sex ( P = .073). Mean improvement in BCVA, central retinal thickness, and total number of injections were similar among the groups at 12 months. Six eyes in the biweekly induction group developed subretinal fibrosis vs no eyes in the other 2 groups ( P = .003).
Conclusion
Biweekly induction with intravitreal bevacizumab for treatment-naïve neovascular AMD does not increase initial fluid-free interval or cause significant anatomic and functional benefit compared to monthly induction or immediate prn. There is also the potential development of subretinal fibrosis with biweekly induction.
Anti–vascular endothelial growth factor (VEGF) is the standard-of-care treatment for neovascular age-related macular degeneration (AMD) owing to its antiangiogenic and antipermeability effects. Ranibizumab and bevacizumab are 2 drugs used worldwide in the treatment of neovascular AMD. Aflibercept, a VEGF receptor fusion protein, is another anti-VEGF agent that received Food and Drug Administration (FDA) approval in November 2011 for the management of neovascular AMD. A patient-tailored treatment regimen is currently favored in order to reduce the number of injections. This usually starts with an “induction” of 3 consecutive monthly injections followed by monthly follow-up with “as-needed” treatment or a “treat-and-extend” strategy. Preference for this induction sequence stems from the view that prompt control of choroidal neovascular activity early in the course of treatment leads to better visual acuity outcome.
Despite the success of this treatment, some cases show resistence. More frequent anti-VEGF injections (every 2 weeks) was effective in eyes with macular fluid refractory to monthly dosing. The possible elevated trough levels with such an intensive regimen may be the reason for improved response in these resistant cases. Taking this into consideration, such an intensive sequence for treatment-naïve eyes during the induction phase may be an attractive idea. Increased intravitreal anti-VEGF concentrations early in the course of treatment may initially control the choroidal neovascular process more effectively, which may translate to prolonged fluid-free intervals, fewer injections, and more rapid functional and anatomic improvement.
In this study, we explored the benefit of an aggressive induction sequence using intravitreal bevacizumab for management of neovascular AMD. We compared induction with 3 consecutive injections every 2 weeks to the more traditional induction of 3 consecutive monthly injections and to an immediate “as-needed” regimen after the first injection, similar to the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Methods
The study was conducted at the American University of Beirut Medical Center and was approved by the institutional review board at the American University of Beirut Medical Center and was in adherence to the tenets of the Declaration of Helsinki. All patients signed a study consent form to participate in this study in which the procedure and treatment options were explained thoroughly. Patients were also reminded of the off-label use of intravitreal bevacizumab. Patients with treatment-naïve neovascular AMD were enrolled prospectively if they met the eligibility criteria. All participants had to be older than 50 years with subfoveal choroidal neovascular membrane (CNV) attributable to AMD diagnosed by fluorescein angiography. Patients were required to have best-corrected visual acuity (BCVA) of 50 letters or better (20/100 Snellen equivalent or better) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Additionally, presence of subretinal fluid, cystic maculopathy, or central retinal thickness >250 μm had to be documented on optical coherence tomography (OCT) with CNV less than 5400 μm in greatest linear dimension. All patients had to understand and sign the study consent form. Exclusion criteria were any of the following: prior treatment for CNV; submacular hemorrhage or scarring involving the fovea; corneal, lenticular, or vitreous opacification that prevents good-quality angiograms or OCT; history of uveitis; history of vitrectomy; proliferative diabetic retinopathy; and other ocular conditions that affect vision. Patients with cardiovascular, cerebrovascular, or peripheral vascular event less than 6 months prior to enrollment were also excluded. All CNV lesion types were included except for retinal angiomatous proliferation and polypoidal choroidal vasculopathy, since they may respond differently to treatment. If both eyes of the same patient were eligible to enter the study, then the eye with the worse visual acuity was enrolled.
Patients were randomized in a 1:1:1 ratio to 1 of 3 groups based on the induction sequence. The biweekly induction group received an injection every 2 weeks for a total of 3 injections. The monthly induction group received consecutive monthly injections for a total of 3 injections. The immediate pro re nata (prn) group did not receive a fixed induction sequence and was treated on an as-needed basis after the first injection.
Baseline Evaluation
Baseline evaluation included BCVA, slit-lamp examination of the anterior segment, dilated fundus examination, fluorescein angiography (FA), and spectral-domain OCT. Eyes with clinical, fluorescein angiographic, or OCT characteristics suggestive of retinal angiomatous proliferation or polypoidal choroidal vasculopathy had indocyanine green angiography to more accurately ascertain these 2 lesion types and exclude them from the study. Visual acuity testing was done according to the ETDRS refraction protocol using ETDRS charts at 4 meters with an illuminated cabinet (Precision Vision, La Salle, Illinois, USA).
One millimeter central retinal thickness was determined by spectral-domain OCT (Cirrus; Carl Zeiss Meditec, Dublin, California, USA) using a macular cube (512 × 128 lines). The internal limiting membrane and retinal pigment epithelium (RPE) lines were identified automatically by the algorithms of the OCT machine, which then calculated the thickness between these layers. The boundaries were confirmed by 2 investigators (Z.F.B. and M.A.) and corrected using the “edit layers” function if the algorithms incorrectly traced the actual boundaries. If the patient had difficulty fixating, the scan pattern in the fundus viewport was manually centered at the fovea. Only good-quality examinations with a signal strength of 6/10 or better were retained and analyzed. The “Repeat Set-up” option was used to acquire subsequent OCT scans during future follow-ups in order to place the scan as close as possible to the initial examination. High-definition 5-line raster scan centered on the fovea was also obtained to further enhance qualitative assessment of the central macular area. In addition, the treating physician had the option to do high-definition scans of any suspicious areas of the macula that were not clear on the cube scan.
Initial and Follow-up Treatment
All patients in the 3 groups received the first intravitreal bevacizumab injection (Avastin; Roche, Basel, Switzerland) and were followed monthly. At each follow-up, BCVA, slit-lamp examination, dilated fundus examination, and OCT were performed. Fluid in the macula was defined as intraretinal cysts or subretinal fluid. A fluid-free macula was considered if there was absence of intraretinal or subretinal fluid on OCT. Response to treatment on OCT was described as: (1) complete response if there was total absence of fluid in the macula; (2) partial response if there was a decrease of at least 50% in central retinal thickness with persistent macular fluid; (3) minimal response if there was a decrease of less than 50% in central retinal thickness with persistent macular fluid; and (4) no response if there was no change or increase in macular fluid. FA was repeated at the discretion of the treating physician.
In the case of the biweekly and monthly induction groups, the “initial fluid-free interval” was the number of months the eye remained fluid free after the completion of the first 3 injections of the induction sequence. The “initial fluid-free interval” for the immediate prn group was determined from the last injection after which the macula became fluid free. If the macula in any of the groups did not show an absence of fluid on OCT after the third consecutive injection, then the “initial fluid-free interval” was considered to be zero.
After the mandatory first 3 injections for the biweekly and monthly induction groups or the first injection in the immediate prn group, follow-up continued every month and retreatment was based on the following criteria: (1) recurrence or presence of any fluid in the macula on OCT in a previously dry macula; (2) an increase in OCT central retinal thickness of at least 25 μm from the lowest recorded value, especially for eyes with persistent macular fluid; (3) visual acuity loss of at least 5 letters with OCT evidence of fluid in the macula; (4) new macular hemorrhage or (5) new area of classic CNV; (6) appearance or increase in size of a retinal cyst or subretinal fluid; and (7) appearance of a new or increase in size of previously existing retinal pigment epithelial detachment (PED). Persistent and stable PED on OCT was not a retreatment criterion.
Adverse Events
Ocular adverse events were defined as sudden loss of 30 letters or more in BCVA, endophthalmitis, vitreous hemorrhage, retinal detachment, cataract formation or progression, intraocular inflammation, and intraocular pressure persistently above 21 mm Hg. Systemic adverse events were defined as elevation of arterial blood pressure by more than 10 mm Hg, stroke, myocardial ischemic event, and peripheral thrombotic events.
Statistical Analysis
The main aim of the study was to assess whether increasing the frequency of bevacizumab injections (ie, every 2 weeks) during the induction phase may better stabilize the neovascular process by prolonging the initial fluid-free interval. Secondary outcome measures were total number of injections over 12 months, improvement in BCVA and central retinal thickness, and the percentage of eyes with a dry macula. Based on data pooled from our records, the initial fluid-free interval after the induction sequence was between 3 and 4 months with an average of 3.4 months and standard deviation of 2 months. We calculated that 30 patients in each of the 3 groups would give 90% power and a significance level of 5% to detect a small effect size in the magnitude of 0.15 for the initial fluid-free interval using 1-way analysis of variance (ANOVA).
Baseline comparisons of both demographic and clinical variables were performed. ANOVA, followed by the Bonferroni pairwise comparison method when needed, was used for numeric variables such as age, visual acuity, and central retinal thickness. For sex, the χ 2 test was used for overall and pairwise comparisons along with the Bonferroni adjustment for the significance level. Within-group changes in BCVA and central retinal thickness were evaluated using the paired t test. Finally, between-group comparisons for the variables initial fluid-free interval, number of injections, and change in BCVA and central retinal thickness at 4 weeks after induction and at 12 months were all done using ANOVA, followed by the Bonferroni method of pairwise comparisons when needed. The percentage of patients who gained 15 or more letters, who lost more than 15 letters, or who were poor responders were compared between the 3 groups, using the χ 2 test and Fisher exact test with similar analysis for pairwise comparisons when needed and adjusting significance level using the Bonferroni method. All analyses were done using Statistical Package for Social Sciences (SPSS, version 17; SPSS Inc, Chicago, Illinois, USA).
Results
Between September 2010 and 2012, 90 eyes of 90 patients who met the inclusion criteria were enrolled in this study and randomized into 1 of the 3 study groups. Patients had an average age of 76.7 years (range, 56 to 90 years), with the majority being male (54.4%; 49/90). At baseline there were no significant differences in age, BCVA, or central retinal thickness between the 3 groups. However, sex distribution was different between the 3 study arms ( P = .003). In particular, there were significantly more female patients recruited to the monthly induction arm as compared to the biweekly induction arm ( P = .001). There was no significant difference among the 3 groups regarding the distribution of lesion type. Table 1 summarizes the demographics of the 3 groups. All patients were followed up for 12 months.
| Immediate As-Needed | Monthly Induction | Biweekly Induction | P Value | |
|---|---|---|---|---|
| Age (SD) | 77.6 (7.4) | 78.2 (6.9) | 74.3 (8.2) | .098 |
| Female sex (%) | 12 (40.0%) a,b | 21 (70.0%) a | 8 (26.7%) b | .003 c |
| Baseline BCVA in letters (SD) | 61.3 (8.8) | 61.8 (17.9) | 60.6 (13.5) | .952 |
| Baseline CRT in μm (SD) | 329.7 (48.4) | 325.3 (54.1) | 328.8 (61.2) | .948 |
| Predominantly classic lesion type (%) | 12 (40) | 9 (30) | 12 (40) | .9 |
| Minimally classic lesion type (%) | 10 (33.3) | 11 (36.7) | 9 (30) | .14 |
| Pure occult lesion type (%) | 8 (26.7) | 10 (33.3) | 9 (30) | .09 |
a,b Same letters indicate no significant difference while different letters indicate significant pairwise difference using Bonferonni correction.
Visual acuity at 12 months increased significantly within each study arm. Mean baseline BCVA was 60.6 letters in the biweekly induction group, which improved 6.2 letters at 12 months to 66.8 letters ( P = .008). Mean baseline BCVA was 61.8 letters in the monthly induction group, which increased by 8.0 letters to 69.8 letters at 12 months ( P < .001). Mean baseline BCVA was 61.3 letters in the immediate prn group and improved 8.3 letters to 69.6 letters at 12 months ( P < .001). None of the eyes in any of the 3 groups had loss of more than 15 letters of visual acuity. There was a gain of 15 or more letters in 6 of 30 eyes (20.0%) in the biweekly induction, 12 of 30 eyes (40.0%) in the monthly induction, and 10 of 30 eyes (33.3%) in the immediate prn group ( P = .234).
Central retinal thickness decreased significantly for all groups after 12 months. Mean baseline central retinal thickness was 328.8 μm in the biweekly induction group and decreased 63.2 μm to 265.6 μm at 12 months ( P < .001). Mean baseline central retinal thickness was 325.3 μm in the monthly induction group, which decreased 65.6 μm by 12 months to 259.7 μm ( P < .001). Mean baseline central retinal thickness was 329.7 μm in the immediate prn group and decreased by 80.2 μm to 249.4 μm at 12 months ( P < .001).
There were no significant differences between the 3 study arms with respect to mean improvement in BCVA and central retinal thickness 1 month after induction and at 12 months ( Figures 1 and 2 ). The immediate prn group did not have a set induction sequence, but they required an average of 2.6 injections to achieve a fluid-free macula at the initiation of treatment. Therefore, we used mean BCVA and central retinal thickness values at month 3, just as with the monthly induction group, in order to simplify the analysis. Table 2 compares the outcomes of the 3 treatment arms.
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