Purpose
To determine the optimal time for administration of intravitreal ranibizumab injections before photodynamic therapy (PDT) as combined therapy to treat polypoidal choroidal vasculopathy (PCV).
Design
Retrospective, comparative, interventional case series.
Methods
The study included 99 eyes (98 patients) with treatment-naïve subfoveal PCV treated with an intravitreal ranibizumab injection followed by PDT. The combination therapy included 1 ranibizumab injection administered 7 days before PDT (7-day group) or 2 days before PDT (2-day group). All eyes were followed for over 12 months.
Results
Intravitreal ranibizumab was administered 7 days before PDT in 59 eyes and 2 days before PDT in 40 eyes. In the 7-day group, the best-corrected visual acuity (BCVA) did not improve significantly at 3 months ( P = .086) or 12 months ( P = .259) compared with baseline. In the 2-day group, BCVA improved significantly at 3 months ( P < .001) and 12 months ( P < .001). The polypoidal lesions regressed completely in 46 eyes (78.0%) in the 7-day group and in 34 eyes (85.0%) in the 2-day group; 38 eyes (64.4%) and 35 eyes (87.5%), respectively, did not require additional treatment, which differed significantly ( P = .008) between the 2 groups. Subretinal hemorrhages did not develop in either group within 1 month after the combined therapy.
Conclusions
Administration of an intravitreal ranibizumab injection 2 days before PDT achieves significantly better visual outcomes and requires fewer additional treatments compared with administration of the injection 7 days before PDT.
Polypoidal choroidal vasculopathy (PCV) is characterized by recurrent serosanguineous detachments of the retinal pigment epithelium (RPE) and peculiar choroidal vascular lesions comprised of polypoidal lesions and branching vascular networks. The incidence of PCV is higher in Asian than in white individuals, and several studies have reported that PCV accounts for 10% to 54% of eyes with presumed exudative age-related macular degeneration (AMD).
Photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis Pharma, Tokyo, Japan) is more effective for treating PCV than choroidal neovascularization (CNV) secondary to AMD. However, polypoidal lesions have high recurrence rates over long periods. PDT is associated with the risk of unexpected massive submacular hemorrhages in PCV. After anti–vascular endothelial growth factor (VEGF) drugs were introduced, intravitreal injections of bevacizumab (Avastin; Genentech, Inc., South San Francisco, California, USA) or ranibizumab (Lucentis; Novartis Pharma, Tokyo, Japan) have been administered to treat PCV. Anti-VEGF drugs reduced exudative fluid, but the vascular lesions did not regress. Combination therapy of verteporfin and ranibizumab, first used to treat neovascular AMD, was an effective treatment for improving visual acuity (VA), reducing complications and requiring fewer additional treatments than PDT monotherapy or anti-VEGF monotherapy.
Recently, when PDT was combined with ranibizumab for treating PCV, the strategy was found to be effective and safe. However, the treatment modalities used in previous studies have differed, making it difficult to evaluate the optimal modality. We previously reported the efficacy of PDT combined with intravitreal injections of bevacizumab 7 days before PDT; however, Gomi and associates reported the efficacy of bevacizumab 1 day before application of PDT. The optimal interval between intravitreal injection of anti-VEGF agents and PDT is controversial. The molecular size of ranibizumab, a Fab fragment, is 48 kDa, and that of bevacizumab, which is a complete antibody, is 149 kDa. Because of its smaller size, ranibizumab may penetrate into the deeper choroidal layer. Bakri and associates reported that in an experimental rabbit study the vitreous half-life of 0.5 mg intravitreal ranibizumab was 2.88 days, which is shorter than the half-life of 1.25 mg bevacizumab of 4.32 days. In a pharmacokinetic study in human eyes, Krohne and associates reported that 1 intravitreal bevacizumab injection had an elimination half-life of 9.82 days. Because of the shorter half-life, if ranibizumab was injected 7 days before PDT, the effect of intravitreal ranibizumab on the upregulated VEGF induced by PDT may be lost. The aim of the current study was to compare the efficacy of PDT and intravitreal ranibizumab for PCV with different intervals between the injections of bevacizumab and application of PDT.
Methods
Patients
The Institutional Review Board at Gunma University Hospital approved the retrospective review of patient data for age-related macular degeneration, and this study followed the tenets of the Declaration of Helsinki. Each patient provided written informed consent before treatment. A total of 98 Japanese patients with treatment-naïve subfoveal PCV were treated with PDT and intravitreal injections of ranibizumab (0.5 mg/0.05 mL) and followed for 12 months. The initial treatments were chosen based on the time period: from April 8, 2009 through January 13, 2010, 1 intravitreal injection of ranibizumab was administered 7 days before PDT (7-day group); and from January 15, 2010 through June 25, 2010, 1 intravitreal injection of ranibizumab was administered 2 days before PDT (2-day group) to treat consecutive patients who agreed to the use of verteporfin and ranibizumab.
The inclusion criteria for this study were patient age older than 50 years; symptomatic subfoveal PCV diagnosed when ophthalmoscopy revealed red-orange subretinal lesions, hemorrhagic RPE detachment, or macular serous retinal detachment secondary to subretinal exudates or hemorrhage; a best-corrected VA (BCVA) of 1.0 or worse; a greatest linear dimension (GLD) of 5400 μm or less; and a minimal follow-up of 12 months after the initial treatment. The exclusion criteria were CNV caused by other diseases, such as pathologic myopia (spherical equivalent ≤−6 diopters); any contraindications to fluorescein angiography (FA), indocyanine green angiography (ICGA), verteporfin, or ranibizumab; the presence of a retinal pigment epithelial tear; uncontrolled hypertension; and a recent myocardial infarction or cerebral vascular accident. The diagnosis of PCV was established based on the finding of polyp-like choroidal vessel dilation with a branching vascular network on ICGA using a scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2 [HRA2]; Heidelberg Engineering, Heidelberg, Germany).
Assessments
All patients underwent a comprehensive ophthalmologic examination, including measurement of the BCVA (Landolt ring test), slit-lamp biomicroscopy with or without a contact lens, FA, ICGA using HRA2, and spectral-domain optical coherence tomography (OCT) (Cirrus OCT; Carl Zeiss Meditec, Dublin, California, USA, or Spectralis OCT; Heidelberg Engineering). The central retinal thickness (CRT), defined as the distance from the RPE to the inner limiting membrane at the center of the fovea, was measured using internal caliper software. FA and ICGA were performed every 3 months until the PCV lesions regressed completely, after which time FA and ICGA were performed when new exudative changes or new hemorrhages were seen on slit-lamp biomicroscopy or OCT during monitoring of the clinical course. The polypoidal lesions were classified with the following grades based on the ICGA findings: complete regression, no polyps seen on imaging; partial regression, greater than a 10% decrease in the size of the area of polyps compared with baseline; no change, a 10% or less change in the size of the area of polyps compared with baseline; and increased size, a greater than 10% increase in the size of the area of polyps compared with baseline.
After the initial combined therapy with PDT and 1 intravitreal injection, patients underwent a comprehensive ophthalmic examination, OCT, and ICGA, if necessary, every month until 12 months after the first treatment.
Any serious adverse events related to the initial treatment were recorded. Because subretinal hemorrhages are the major adverse event associated with PDT for PCV, the incidence rates of new subretinal or subpigment epithelial hemorrhages exceeding 1 disc diameter and vitreous hemorrhages that developed between 1 and 12 months after the initial treatment were determined.
Treatment
The initial treatment included 1 intravitreal ranibizumab injection 7 days or 2 days before PDT. Intravitreal ranibizumab (0.5 mg/0.05 mL) was injected into the vitreous cavity 3.5 mm posterior to the corneal limbus using a 30-gauge needle after application of a topical anesthetic drug. PDT with verteporfin was administered using the standard dose (6 mg/m 2 ) according to the protocol of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy study; a 689-nm laser system (Visulas PDT system 690S, Carl Zeiss) delivered 50 J/mm 2 during an 83-second exposure time, except for the GLD. The GLD of the lesion for laser exposure during PDT was determined based on the ICGA findings in all patients as reported previously. The branching vascular networks and polyps were included in the area treated with PDT. When ICGA showed recurrent or residual polypoidal lesions and OCT showed exudative changes, additional combination therapy of 1 intravitreal injection was given. The minimal interval between PDT treatments was 3 months. When recurrent or residual exudative changes were seen on OCT images, an additional injection of ranibizumab was administered.
Statistical Analysis
The BCVA was measured as the decimal VA using a Landolt chart and converted to the logarithm of the minimal angle of resolution (logMAR) for statistical analysis. The BCVA was considered improved or deteriorated when the change in the logMAR VA exceeded 0.3 unit.
We used the Wilcoxon signed rank test to identify significant changes in the mean BCVA and CRT compared with baseline. We used the χ 2 for independence test and Fisher exact probability test and the Mann-Whitney U test to analyze the proportion of patients with improved or deteriorated VA and polyp regression for significant changes from baseline. P < .05 was considered significant for all tests. Statistical analysis was conducted using SPSS software, version 20.0.0, for Windows (SPSS, Inc, Chicago, Illinois, USA).
Results
Ninety-nine eyes of 98 patients (79 men, 19 women) were included; 59 eyes of 58 patients (48 men, 10 women) were treated initially with combined therapy of ranibizumab 7 days before PDT (7-day group) and 40 eyes of 40 patients (31 men, 9 women) were treated with combined therapy of ranibizumab 2 days before PDT (2-day group). Table 1 shows the patient characteristics in both groups. The baseline factors, including age, sex, initial BCVA (logMAR), lesion GLD, CRT, and the incidence rates of cystoid macular edema, serous retinal detachments, subretinal hemorrhages, and coexisting pigment epithelial detachments, did not differ significantly between treatments.
| 7-Day Group | 2-Day Group | P | |
|---|---|---|---|
| No. of eyes | 59 | 40 | |
| Age (y) | 75.3 ± 7.3 | 73.4 ± 8.2 | .39 |
| Sex (F/M) | 10/48 | 9/31 | .64 |
| Initial BCVA (logMAR) | 0.41 (0.39) | 0.46 (0.35) | .54 |
| Lesion GLD (μm) | 3311 ± 1090 | 2960 ± 1363 | .11 |
| Initial central retinal thickness (μm) | 303.8 ± 137.0 | 322.5 ± 174.6 | .96 |
| Cystoid macular edema, no. (%) | 10 (16.9) | 7 (17.5) | .94 |
| Serous retinal detachment, no. (%) | 52 (88.1) | 34 (85.0) | .65 |
| Subretinal hemorrhage, no (%) | 38 (64.4) | 26 (65.0) | .95 |
| Pigment epithelial detachment, no (%) | 42 (71.1) | 24 (60.0) | .25 |
Best-Corrected Visual Acuity
Figure 1 shows the mean BCVA scores over time. The BCVA in the 7-day group did not improve significantly compared with baseline at 1 week ( P = .871), 1 month ( P = .140), 3 months ( P = .086), 6 months ( P = .218), 9 months ( P = .566), and 12 months ( P = .259) after the initial treatment. In the 2-day group, the BCVA improved significantly at 1 week ( P = .003), 1 month ( P = .002), 3 months ( P < .001), 6 months ( P < .001), 9 months ( P < .001), and 12 months ( P < .001) after the initial treatment. Eyes in the 7-day group gained a mean of 0.03 logMAR unit (0.3 line) and eyes in the 2-day group gained a mean of 0.14 logMAR unit (1.4 lines) at 3 months; at 12 months, the respective gains were 0.07 logMAR unit (0.7 line) and 0.19 logMAR unit (1.9 lines). Three months after treatment, the BCVA improved by 3 lines or more in 7 of 59 eyes (11.9%) in the 7-day group and in 11 of 40 eyes (27.5%) in the 2-day group, a difference that reached significance ( P = .048, χ 2 for independence test) ( Figure 2 ). Twelve months after treatment, the BCVA improved in 14 of 59 eyes (23.7%) and 12 of 40 eyes (30.0%), respectively, a difference that did not reach significance ( P = .487, χ 2 for independence test). Three months after treatment, 54 of 59 eyes (92%) and 39 of 40 eyes (98%), respectively, had improved or stable VA (defined as a loss of 3 or fewer lines of vision), a difference that did not reach significance ( P = .218, Fisher exact probability test) ( Figure 3 ). Twelve months after treatment, 44 of 59 eyes (74.6%) and 40 of 40 eyes (100%), respectively, had improved or stable VA, which was a significant difference ( P = .046, Fisher exact probability test). Three months after treatment, the BCVA decreased in 5 of 59 eyes (8.5%) and 1 of 40 eyes (2.5%), respectively, which was not significant ( P = .219, Fisher exact probability test). The BCVA did not decrease by 3 or more lines in any patients during the follow-up period after the initial treatment in the 2-day group; however, the BCVA decreased in 10 eyes (16.9%) in the 7-day group, a difference that reached significance ( P = .004, Fisher exact probability test).
Optical Coherence Tomography Outcomes
In the 7-day group, the mean CRT decreased significantly ( P < .001 for all comparisons) from 303.8 ± 137.0 μm at baseline to 269.6 ± 131.8 μm at 1 week, 175.7 ± 87.6 μm at 1 month, 157.1 ± 94.3 μm at 3 months, 159.1 ± 77.3 μm at 6 months, 157.6 ± 75.9 μm at 9 months, and 145.6 ± 51.4 μm at 12 months. In the 2-day group, the CRT decreased significantly ( P < .001 for all comparisons) from 322.5 ± 174.6 μm at baseline to 241.9 ± 129.9 μm at 1 week, 192.5 ± 106.3 μm at 1 month, 168.3 ± 84.5 μm at 3 months, 146.1 ± 42.5 μm at 6 months, 142.7 ± 36.4 μm at 9 months, and 148.6 ± 49.6 μm at 12 months ( Figure 4 ).
In the 7-day group, the incidence rates of retinal pigment epithelial detachment decreased significantly ( P < .001 for both comparisons) from 42 of 59 eyes (71.2%) at baseline to 29 (49.2%) at 3 months and 22 (37.3%) at 12 months. The incidence rates of serous retinal detachment decreased significantly ( P < .001 for both comparisons) from 52 of 59 eyes (88.1%) at baseline to 5 (8.5%) at 3 months and 8 (13.6%) at 12 months. The incidence rates of subretinal hemorrhages decreased significantly ( P < .001 for both comparisons) from 38 of 59 eyes (64.4%) at baseline to 2 (3.4%) at 3 months and 4 (6.8%) at 12 months. The incidence rates of cystoid macular edema decreased significantly from 10 of 59 eyes (16.9%) at baseline to 1 (1.7%) at 3 months ( P = .020) and 2 (3.4%) at 12 months ( P = .011).
In the 2-day group, the incidence rates of retinal pigment epithelial detachment decreased significantly ( P < .001 for both comparisons) from 24 of 40 eyes (60.0%) at baseline to 15 (37.5%) at 3 months and 12 (30.0%) at 12 months. The incidence rates of serous retinal detachment decreased significantly ( P < .001 for both comparisons) from 34 of 40 eyes (85.0%) at baseline to 4 (10.0%) at 3 months and 2 (5.0%) at 12 months. The incidence rates of subretinal hemorrhage decreased significantly ( P < .001 for both comparisons) from 26 of 40 eyes (65.0%) at baseline to 0 (0%) at 3 months and 4 (10.0%) at 12 months. The incidence rates of cystoid macular edema decreased significantly from 7 of 40 eyes (17.5%) at baseline to 2 (5.0%) at 3 months ( P = .020) and 1 (2.5%) at 12 months ( P = .011).
Regression of Polyps
After the initial treatment, the polypoidal lesions regressed completely on ICGA in 46 of 59 eyes (78.0%) in the 7-day group ( Figure 5 ) and in 34 of 40 eyes (85.0%) in the 2-day group ( Figure 6 ); the polypoidal lesions regressed partially in 12 of 59 eyes (20.3%) and in 6 of 40 eyes (15.0%), respectively. The polypoidal lesions increased in 1 of 59 eyes (1.7%) and none of 40 eyes (0%), respectively. These results did not differ significantly ( P = .369, Mann-Whitney U test).
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