To investigate the 1-year outcomes of monthly intravitreal injections of ranibizumab for 3 months followed by an as-needed reinjection schedule to treat polypoidal choroidal vasculopathy (PCV) in Japanese patients.
Prospective, consecutive case series.
Eighty-five eyes of 82 consecutive Japanese patients with naïve symptomatic PCV received monthly intravitreal injections of ranibizumab for 3 months followed by an as-needed reinjection schedule. Eighty-one eyes (95%) followed for 1 year were studied.
A mean of 4.2 ± 1.3 (mean ± standard deviation) injections were administered over 1 year. Twenty-three of 81 eyes (28%) did not require additional injections and 32 eyes (40%) required only 1 injection after the 3 monthly injections. The mean (± standard error) logarithm of minimal angle of resolution (logMAR) visual acuity (VA) at baseline was 0.59 ± 0.37 and improved to 0.37 ± 0.30 ( P = .001). Thirty eyes (37%) and 5 eyes (6%), respectively, had improved and decreased VA of 0.3 or more logMAR unit. Indocyanine green angiography showed that the polypoidal lesions resolved in 21 eyes (26%) and 32 eyes (40%) 3 months and 1 year after the first injection, respectively. Abnormal choroidal vessels remained in all eyes.
Monthly injections of ranibizumab for 3 months to treat PCV improved the VA, and a reinjection schedule based on need maintained the improved VA. The polypoidal lesions tended to improve over 1 year, whereas abnormal choroidal vessels remained in all eyes. Further long-term follow-up is needed to determine the efficacy of ranibizumab therapy for PCV.
Photodynamic therapy (PDT) with verteporfin for polypoidal choroidal vasculopathy (PCV) maintains or improves vision. Although in most eyes with PCV the polypoidal lesions initially resolve after PDT, indocyanine green angiography (ICGA) has shown that the branching vascular networks persist in almost all eyes. Recurrent or new polypoidal lesions develop at the terminal branching vascular network during the follow-up period, resulting in visual deterioration. Hemorrhagic complications associated with PDT decrease the visual function. After the MARINA and ANCHOR trials showed that monthly intravitreal ranibizumab (Lucentis, Genentech, South San Francisco, California, USA) injections were superior to PDT with verteporfin and resulted in better visual outcomes and low rates of serious ocular adverse events in exudative age-related macular degeneration (AMD), ranibizumab became the standard therapy for exudative AMD. Kokame and associates recently reported that monthly intravitreal ranibizumab injections were safe, well-tolerated, and stabilized vision in eyes with PCV. We previously reported that monthly intravitreal injections of ranibizumab for 3 months in eyes with PCV improved the visual acuity (VA) and the vascular component on ICGA with a confocal scanning laser ophthalmoscope (cSLO).
The EVEREST study was the first double-masked, randomized controlled trial to assess the effect of PDT alone or in combination with ranibizumab compared with ranibizumab alone in eyes with PCV. A total of 61 Asian patients with PCV participated in the study and were divided into 3 treatment groups, with about 20 eyes in each group. The 6-month results from the EVEREST study showed a significantly higher proportion of complete polyp regression with PDT with or without ranibizumab compared to ranibizumab alone, and the best VA improvement occurred with PDT combined with ranibizumab with no significant differences among the 3 groups ( www.clinicaltrials.gov/ct2/show/NCT00674323?term=polypoidal+choroidal+vasculopathy+verteporfin&rank=1 ). Because PCV has a variety of clinical manifestations, each might have a different natural course. Although a randomized controlled trial is the superior study design, the number of eyes in each group was too small and the 6-month follow-up period was too short to establish the gold-standard therapy for PCV. Rouvas and associates conducted a retrospective comparative study of 30 eyes with PCV and concluded that the results 1 year after PDT were significantly better compared with those of ranibizumab and combined with PDT and ranibizumab. Thus, the treatment strategy for PCV is still debated. To investigate the efficacy of ranibizumab monotherapy for PCV, we conducted a 1-year study of a consecutive series of Japanese patients with PCV treated with a monthly intravitreal injection of 0.5 mg of ranibizumab for 3 months followed by a reinjection schedule based on need.
Patients and Methods
After March 13, 2009, when ranibizumab was approved for use to treat AMD in Japan, all patients with AMD including PCV were treated with an intravitreal injection of 0.5 mg of ranibizumab for 3 months followed by a reinjection schedule based on need at the Ohtsuka Eye Hospital. Eighty-five consecutive eyes of 82 prospective treatment-naïve Japanese patients with symptomatic PCV, who had fluid in the macula such as intraretinal fluid, subretinal fluid, and fluid under the retinal pigment epithelium (RPE), referred to as a pigment epithelial detachment (PED), received ranibizumab therapy. In addition, all patients were required to provide informed consent. There were no exclusion criteria for baseline VA or lesion size. Although PCV was diagnosed based on the fundus findings, ICGA findings, or both followed by the diagnostic criteria defined by the Japanese Study Group of PCV, that is, the presence of elevated orange-red lesions (excluding a PED, choroidal hemangioma, and subretinal blood) observed during a fundus examination or characteristic polypoidal lesions on ICGA, PCV was diagnosed in all eyes after confirmation of the presence of polypoidal lesions on ICGA. Fifty eyes of 50 patients who underwent treatment to determine the efficacy of a monthly injection of ranibizumab for 3 months based on ICGA findings in our previous study were included in the 85 eyes in the current study.
During an initial visit all 85 eyes underwent a complete ophthalmic exam, including VA measurements with the Landolt ring chart, digital simultaneous fluorescein angiography (FA) and ICGA using cSLO (Heidelberg Retina Angiograph II [HRA-2]; Heidelberg Engineering Inc, Dossenheim, Germany), and optical coherence tomography (OCT) (OCT 3000; Zeiss Humphrey Instruments, Dublin, California, USA). Seventy seven of 85 eyes also received first injection of ranibizumab at the initial visit, and the remaining 8 eyes received first injection within a few days after initial examination. The visit during which the preoperative examination was performed was defined as baseline. Six radial line scans through the center of the foveal lesion were used to evaluate whether fluid was present in the macula. The foveal thickness was defined based on the average foveal thickness on the vertical and horizontal scans. The foveal thickness on the vertical and horizontal scans was measured from the inner retinal surface to the RPE line. In eyes with PED, the foveal thickness was defined as the length of the line from the inner retinal surface to the point at right angles to the line between the edges of the elevated RPE. Since it has been reported that automatic measurements of the macular thickness often fail to identify the outer border of the neural retina, we used the manual method.
Ophthalmic examinations including VA measurement and OCT were performed monthly. FA and ICGA also were performed 3, 6, and 12 months after the first ranibizumab injection. The planimetric size of the branching vascular network was measured from the early-phase ICGA images at baseline and 12 months after the first injection. The presence or absence of polypoidal lesions was judged based on the ICGA findings. If no apparent polypoidal lesions were observed, the eyes were defined as having resolved polypoidal lesions.
After intravitreal injection of ranibizumab monthly for 3 months, additional injections were given if any of the following occurred: 1) VA loss of at least 1 line with OCT evidence of fluid at the macula; 2) any qualitative change in the appearance of the OCT images that suggested recurrent fluid in the macula including an enlargement of a PED; 3) new macular hemorrhages; or 4) persistent fluid on OCT 1 month after the previous injection. All criteria were based on comparisons with the previous month’s examination or the last FA and ICGA. If any single criterion for reinjection was fulfilled, the intravitreal injection was performed.
The differences in the VAs between baseline and 12 months after the first injection were analyzed using the paired Student t test. The logarithm of the minimal angle of resolution (logMAR) was used to analyze the VA. Statistical analysis was performed using the SPSS 11.5.1 for Windows software package (SPSS Inc, Chicago, Illinois, USA).
Of 85 consecutive eyes with PCV, 4 eyes (5%) were lost to follow-up. Of the 4 eyes, 2 eyes had massive hemorrhagic events immediately after the first injection and the fundus could not be observed, and vitrectomy was performed. In the other 2 eyes, the follow-up examinations were interrupted after the 3 monthly injections that improved the VA, which reached 0 in logMAR VA (1.0 in decimal VA). Thus, 81 eyes of 78 patients (55 men, 23 women) who could be followed for more than 12 months after the first injection were analyzed. The mean (± standard deviation [SD]) age was 71 ± 9 years (range, 50–84 years). The mean logMAR VA and foveal thickness at baseline were 0.59 and 324 μm, respectively ( Figures 1 and 2 , respectively). OCT showed foveal cysts in 5 eyes (6%), subretinal fluid in 50 eyes (62%), and a PED in 24 eyes (30%) ( Table 1 ).
|OCT Findings||No. (%) Eyes (N = 81)|
|Baseline||3 Months After First Injection||6 Months After First Injection||9 Months After First Injection||12 Months After First Injection|
|Retinal cysts||5 (6)||0 (0)||1 (1)||1 (1)||1 (1)|
|Subretinal fluid||50 (62)||20 (25)||7 (9)||8 (10)||8 (10)|
|PED||24 (30)||14 (17)||16 (20)||17 (21)||15 (19)|
The mean (± SD) number of injections during 1 year was 4.2 ± 1.3. Twenty-three of the 81 eyes (28%) did not require any additional injections, whereas 32 eyes (40%) required 1, 16 eyes (20%) required 2, 7 eyes (9%) required 3, 2 eyes (2%) required 4, and 1 eye (1%) required 5. Table 2 shows the relation between the number of eyes and the timing of the reinjections of ranibizumab after the first injection. One month after the 3 monthly intravitreal injections, 20 eyes (25%) needed an additional injection. The eyes that received a reinjection were distributed equally thereafter.
|Follow-up Interval||No. (%) Eyes (N = 81)|
|3 months after the first injection||20 (25%)|
|4 to 6 months after the first injection||26 (32%)|
|7 to 9 months after the first injection||24 (30%)|
|10 to 12 months after the first injection||28 (35%)|
Figure 1 shows the change in the mean (± standard error [SE]) logMAR VA for 12 months after the first injection. The VA 1 month after the third intravitreal injection (0.40 ± 0.04) significantly improved compared with the baseline VA (0.59 ± 0.04, P = .001) and was maintained thereafter (0.37 ± 0.03 at 12 months after the first injection, P = .001). Figure 2 shows the changes in the mean (± SE) foveal thickness for 12 months after the first injection. The foveal thickness 1 month after the third intravitreal injection (203 ± 7 μm) significantly decreased compared to the foveal thickness at baseline (324 ± 18 μm, P = .001) and was maintained thereafter (211 ± 10 μm at 12 months after the first injection, P = .001). The courses of the changes in VA and foveal thickness were very similar. The findings in the fovea on OCT also improved throughout 12 months after the first injection ( Table 1 ), which was associated with a decreased foveal thickness on OCT.
Figure 3 shows the plots of the logMAR VA at baseline and 12 months after the first injection in each eye. In most eyes, the VAs improved or remained the same for 12 months after the first injection. Thirty of 81 eyes (37%) had an improvement in VA of 0.3 or more logMAR unit, 5 (6%) had a decrease in VA of 0.3 or more logMAR unit, and 46 (57%) had a change in the logMAR VA less than 0.3 unit ( Table 3 ). The relations between the changes in the logMAR VA and the number of reinjections and logMAR VA at baseline are shown in Table 3 . Although the number of eyes with a decreased VA was not large enough to statistically analyze, the number of additional injections in eyes with decreased VA that exceeded 0.3 logMAR unit was significantly higher than in eyes with improved or stable VA ( P = .006 and P = .018, respectively). In eyes with an improved VA, the baseline VA was significantly worse than in eyes with stable or decreased VA ( P = .001 and P = .002, respectively). Of the 5 eyes with a decreased VA, a subretinal hemorrhage that included the fovea was present at baseline in 2 eyes, an RPE tear extended to the fovea in 2 eyes, and foveal atrophy developed in 1 eye. Those episodes were thought to cause serious decreases in the VA.
|Suspected Factors Associated With Changes in VA a|
|Changes in logMAR VA||No. (%) Eyes (N = 81)||No. Reinjections (SD)||Baseline logMAR VA (SE)|
|0.3 ≤ improved logMAR VA||30 (37)||1.16 (0.95)*||0.84 (0.06) §|
|Less than 0.3||46 (57)||1.09 (1.03) †||0.45 (0.09) ∥|
|0.3 ≤ decreased logMAR VA||5 (6)||2.60 (1.52) ‡||0.33 (0.10) ¶|
At baseline, classic choroidal neovascularization (CNV) associated with PCV was found in 5 of 81 eyes (6%). In all 5 eyes, classic CNV showed scar formation after 3 monthly ranibizumab injections and did not recur throughout the follow-up period in this study. The mean number of injections during 1 year was 4.0 ± 0.7 in the 5 eyes, which was not significantly different between PCV eyes with and without classic CNV. Neither new classic nor occult CNV developed during the follow-up period.
The baseline ICGA showed polypoidal lesions and abnormal choroidal vessels in all eyes except 4 eyes in which the abnormal choroidal vessels were not detected because of retinal and subretinal hemorrhages. Figure 4 shows the changes in the percentages of the 81 eyes in which polypoidal lesions resolved on ICGA throughout 12 months after the first injection. ICGA performed 3 months after the first injection showed that the polypoidal lesions were no longer discernible in 21 eyes (26%). The polypoidal lesions that were not detected in 18 eyes (22%) 3 months after the first injection did not recur on ICGA 12 months after the first injection ( Figure 4 ). In the 60 eyes (74%) in which the polypoidal lesions were detected on ICGA 3 months after the first injection, 14 (14/60, 23%) had no detectable polypoidal lesions on ICGA 12 months after the first injection. Thus, ICGA 12 months after the first injection showed that the polypoidal lesions were not detected in 32 eyes (39%). However, abnormal choroidal vessels remained in all eyes in which abnormal choroidal vessels were detected at baseline. Of the 77 eyes in which abnormal choroidal vessels were detected at baseline, the planimetric size of the abnormal choroidal vessels 12 months after the first injection increased more than 20% compared with that at baseline in 9 eyes (12%) and decreased more than 20% compared with that at baseline in 3 eyes (4%); a change in lesion size of less than 20% occurred in 65 eyes (84%). In 21 of 81 eyes (26%) in which the polypoidal lesions were no longer discernible on ICGA performed 3 months after the first injection, the mean logMAR VAs at baseline and 3 and 12 months after the first injection were 0.57 (SE, 0.05), 0.41 (0.06), and 0.36 (0.03), which were not different compared with those in eyes in which polypoidal lesions were observed on ICGA 3 months after the first injection: 0.60 (0.04), 0.38 (0.05), and 0.37 (0.03), respectively. The mean (± SD) number of additional injections after the monthly injections administered for 3 months out to 12 months after the first injection in the 21 eyes was 0.6 ± 0.9, which was significantly smaller compared to that (1.4 ± 1.5) in the eyes in which polypoidal lesions were observed on ICGA 3 months after the first injection ( P = .001). In all 3 eyes in which polypoidal lesions that were not detected 3 months after the first injection recurred 12 months after the first injection, additional injections were necessary after the recurrence of the lesions: 2 eyes required 2 injections and 1 eye required 1 injection. However, 6 of the 21 eyes in which the polypoidal lesions resolved 3 months after the first injection and did not recur throughout the follow-up period required additional injections: 3 eyes required 1 injection, 2 eyes required 2 injections, and 1 eye required 3 injections. In those eyes, the vascular hyperpermeability from the abnormal choroidal vessels induced subretinal fluid and/or retinal edema.