Background/aims To compare the short-term efficacy of intravitreal aflibercept treatment according to the subtypes of polypoidal choroidal vasculopathy (PCV) based on indocyanine green angiography (ICGA).
Methods Twenty-nine patients (29 eyes) with treatment-naïve subfoveal PCV were consecutively enrolled in this institutional study. The subjects were classified into two subtypes (type 1, polypoidal choroidal neovascularisation (CNV), 16 eyes; and type 2, idiopathic PCV, 13 eyes) based on the presence or absence of both feeder and draining vessels on ICGA. Intravitreal aflibercept was administered at baseline and at 1, 2 and 4 months. The primary outcome was the polyp regression percentage after 3 monthly injections. Changes in the best-corrected visual acuity and subfoveal choroidal thickness (CT) were evaluated at 3 and 6 months.
Results The complete polyp regression percentage was higher in type 1 than type 2 patients after 3 monthly injections (81% vs 30%, p=0.008). Type 1 patients showed better visual improvement at 3 months (−0.34 vs −0.08 logarithm of the minimum angle of resolution (logMAR), p=0.050) and 6 months (−0.30 vs −0.10 logMAR, p=0.168) than type 2 patients. Although subfoveal CT was significantly decreased after injections in both groups, type 2 patients with a thicker choroid at baseline showed a greater decrease than type 1 patients (p=0.032).
Conclusions There was a difference in early treatment response with aflibercept between two subtypes of PCV. Type 1 polypoidal CNV showed better visual improvement with a higher percentage of polyp regression than type 2 idiopathic PCV.
Trial registration number NCT02597855, Results.
- Treatment Medical
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Polypoidal choroidal vasculopathy (PCV) is a vascular disease characterised by serosanguineous detachments of retinal pigment epithelium (RPE) and neurosensory retina.1 With the use of indocyanine green angiography (ICGA), characteristic polypoidal lesions and abnormal branch vascular networks (BVNs), essential for PCV diagnosis, can be observed;2 various morphological features of PCV have been reported.
Several recent studies have suggested that there are two representative angiographic subtypes of PCV.3–5 The first is a polypoidal choroidal neovascularisation (CNV) associated with neovascular age-related macular degeneration (NV-AMD). It was suggested that polypoidal lesions are terminal dilations of CNV located between the RPE and Bruch's membrane. Using ICGA, Kawamura et al3 reported that this type of PCV has a feeder vessel and a subsequent draining vessel. The second is an idiopathic PCV in which the polypoidal lesions are related to inner choroidal vessel abnormalities constituting the branch vascular network (BVN).6 The BVN of type 2 PCV was reported to show slow filling on ICGA.3
Due to the distinct characteristics of the two subtypes, it is expected they have different pathophysiology, genetic backgrounds and disease progressions. One comparative study reported the treatment outcomes of photodynamic therapy (PDT) between the two subtypes.7 To our knowledge, no study has reported the treatment efficacy of anti-vascular endothelial growth factor (VEGF) on the two subtypes of PCV. In the present study, PCV was classified based on ICGA findings: (1) polypoidal CNV (type 1) and (2) idiopathic PCV (type 2), and the treatment effects of anti-VEGF were compared. Aflibercept, which has been reported to be highly effective for polyp closure in PCV,8 was used as the anti-VEGF treatment option.
Materials and methods
This was a prospective cohort study conducted at Yeungnam University Hospital in Daegu, South Korea. The protocol of the study was approved by the Institutional Review Board of Yeungnam University Medical Center, and registered at ClinicalTrials.gov with identification number NCT02597855. This study adhered to the Declaration of Helsinki, and written informed consent was obtained from all patients.
Patients with subfoveal PCV accompanying a BVN were recruited consecutively from 1 September 2015 to 31 March 2016. A diagnosis of PCV was confirmed by a retinal specialist (MS) using a dilated fundus examination, optical coherence tomography (OCT) and ICGA. Exclusion criteria were the following: (1) retinal diseases other than PCV, (2) massive subretinal haemorrhage or fibrosis blocking polyps and a BVN on ICGA, (3) severe media opacity, and (4) a previous history of intraocular surgery or intravitreal injection. Cataract surgery performed more than 3 months previously was not considered an exclusion criterion.
Treatment was initiated either the same day or within 1 week after enrolment. The patients were treated with an intravitreal aflibercept (2.0 mg) injection every month for the first 3 months (at initial visit, 1 and 2 months). During the rest period, one additional injection was administered at 4 months.
Baseline and follow-up examinations
At the baseline visit, patients received a comprehensive ophthalmic examination including a best-corrected visual acuity (BCVA) measurement, a dilated fundus examination, spectral domain OCT (SD-OCT, Spectralis; Heidelberg Engineering, Heidelberg, Germany), and fluorescein angiography (FA) and ICGA using a Heidelberg Retinal Angiograph II (Heidelberg Engineering).
Patients were examined monthly for the entire period of the study. Measurement of BCVA and SD-OCT was performed at each visit. ICGA was performed initially and 1 month after the third aflibercept injection. BCVA was measured using the Snellen chart and recorded using the logarithm of the minimum angle of resolution (logMAR) scale.
The primary outcome was the percentage of polyp regression after 3 monthly injections. FA and ICGA performed initially and at 3 months were used to determine the polyp number and size, greatest linear dimension (GLD), BVN leakage, and to evaluate polyp regression. On SD-OCT, central macular thickness (CMT), largest pigment epithelium detachment (PED) height, and subfoveal choroidal thickness (CT) were measured manually at each visit. A dry macula on SD-OCT was also investigated.
Subject classification was performed at the end of the study to avoid bias during measurements of clinical data. All cases were classified by a retinal specialist (MS) into two subtypes involving polypoidal CNV (type 1 PCV) and idiopathic PCV (type 2 PCV). Next, a trained ophthalmologist (SJ) conducted a second classification. While conducting the classification, they were blinded to the subject's clinical history, clinical outcomes and each other's assessment. To resolve differences of classification, they reviewed the discrepancies in open adjudication and arrived at a consensus. According to the angiographic classification proposed by Kawamura et al,3 the existence or non-existence of feeder and drainage vessels on ICGA was checked. Subjects having feeder vessels showing contrast enhancement immediately after filling of the choroidal arterioles, and having gradually brightening draining vessels, were defined as type 1 PCV. Type 1 PCV was characterised by multiple polypoidal dilatations at the termini of prominent BVNs extending from feeder vessels. Patients who did not have either a feeder or draining vessel, but had a BVN that showed slow filling were defined as type 2 PCV. Type 2 PCV was characterised by a weak BVN and a few polyps (figure 1).
Statistical analyses were performed using IBM SPSS V.20.0 for Windows (IBM Co., Armonk, New York, USA). The Mann–Whitney test was used for a comparison of numerical variables between two subgroups. BCVA, largest polyp diameter, largest PED height, CMT and subfoveal CT measured after aflibercept injections were compared with baseline using the Wilcoxon signed-rank test in each subgroup. Categorical variables were compared between two groups using the χ2 test or Fisher's exact test. Variables with a p value <0.05 were considered statistically significant.
A total of 32 eyes from 32 patients were included at the initial visit. Three patients failed to complete the 6-month follow-up. Of the 29 patients who completed all visits, 16 (55.2%) were diagnosed with type 1 and 13 (44.8%) were diagnosed with type 2. The inter-grader agreement of angiographic classifications was excellent (κ value=0.931).
The baseline characteristics showed no significant difference in age, gender, BCVA, largest polyp diameter, GLD, largest PED height, and CMT between the two subgroups. Type 1 patients had more polyps than type 2 patients (3.8±2.2 vs 1.6±0.8, p=0.001). The frequency of BVN leakage was higher in type 1 than in type 2 patients (87.5% vs 46.2%, p=0.023). The subfoveal CT of type 1 patients was thinner than that of type 2 patients (206.9±57.8 vs 275.1±82.5 μm, p=0.015; table 1).
Polyp closure percentage
After 3 monthly injections, for type 1 patients, 13 (81.2%) of 16 eyes achieved complete regression and three eyes (18.8%) showed partial regression. There were no patients showing an absence of polyp regression in the type 1 subgroup. In the type 2 subgroup, four (30.8%) of 13 eyes achieved complete regression, seven eyes (53.8%) showed partial regression, and two eyes (10%) were unchanged. Overall, type 1 patients showed a significantly higher complete regression percentage than type 2 patients (p=0.008; table 2).
At 3 months, the BCVA was significantly improved in type 1 patients, but not in type 2 patients (table 3). Greater improvement of BCVA was observed in type 1 than in type 2 patients (−0.36±0.30 vs −0.08±0.19, p=0.036; table 2).
At 6 months, BCVA improvement was still significant in type 1, but not in type 2 patients. The BCVA that showed more improvement in type 1 patients at 3 months than type 2 patients no longer showed a significant difference at 6 months (figure 2).
At 3 months, the largest PED height, the largest polyp size and CMT decreased regardless of the subtypes (table 3). Despite greater improvement of these anatomical parameters in type 1 than type 2 patients, there was no significant difference in the changes between the two subgroups. The response of subfoveal CT was more pronounced in type 2 than in type 1 patients (−19.6±22.8 vs −43.5±27.9 μm, p=0.032). The percentage of dry macula at 3 months was greater in type 1 than in type 2 patients, but there was no significant difference (table 2).
At 6 months, both subgroups showed a significant decrease of the largest PED height, the CMT and the subfoveal CT compared with baseline. There was no significant difference in changes between the two groups (figure 2). The percentage of dry macula at 6 months showed no significant difference (p=0.135).
No systemic or ocular adverse effects were noted.
This study compared the short-term treatment outcomes of anti-VEGF treatment between subtypes of PCV based on angiographic characteristics. Type 1 PCV showed a better response to aflibercept than type 2 PCV in polyp regression and BCVA improvement. The different treatment effects may be due to their different pathophysiology and genetic backgrounds.
A polypoidal lesion confirmed on ICGA is not a single disease entity, but appears to result from multiple vascular abnormalities. Two different vascular structures of PCV were described by previous histopathological studies. The first involved a neovascular membrane located between the RPE and Bruch's membrane.9 The second was the aneurysmal dilatation of inner choroidal vessels, characterised by degenerative hyalinisation of the inner vascular wall.10 With the recent development of imaging instruments such as the scanning laser ophthalmoscope for ICGA and SD-OCT, the location of polyps and their origins can be identified in vivo. Kawamura et al3 classified PCV into polypoidal CNV and idiopathic PCV based on their characteristic features on ICGA. As a result, the two types were divided by the existence or non-existence of CNV and were correlated with the histopathological subdivisions. The similarity of the CNV component between type 1 PCV and NV-AMD can possibly explain the better response to anti-VEGF treatment compared with the response of type 2 PCV.
Type 2 PCV may differ from NV-AMD. A comparative study analysing the aqueous humour of patients with PCV and NV-AMD reported that those with PCV have higher aqueous humour VEGF levels than the normal control group, but a lower level than that of patients with NV-AMD.11 Some clinical studies reported that PCV shows better treatment outcomes than PDT and is less responsive to anti-VEGF than typical AMD.12
Based upon these reports, PCV may consist of two or more disease types, with type 1 sharing a common pathogenic background with NV-AMD, compared with PCV of the more specifically defined type 2. Their difference could be confirmed by distinct baseline characteristics. Consistent with the present study, type 1 was reported to show more polyps than type 2. Kawamura et al3 reported that feeder vessels of type 1 continued to radiating network vessels, and their terminal portions formed numerous polyps. The polyps in type 2 appeared to involve bulging of choroidal vessels, and most cases of type 2 had only one polyp.3 Another report on PCV classification reported that type 1 had more polyps than type 2.5 Leakage on FA was reported for both polyps and BVN of type 1 patients, but only for polyps of type 2 patients.4 We found a similar result indicating that type 1 patients showed more BVN leakage, suggesting CNV characteristics. Consistent with previous studies classifying PCV,3 ,4 the present study, showed that the baseline subfoveal CT was thicker in type 2 than type 1 patients. Chung et al13 reported thicker CT in PCV patients compared with NV-AMD patients. Bulging of choroidal vessels of type 2 suggests increased choroidal pressure or stasis of choroidal blood flow, with subsequent choroidal thickening.
Different genetic backgrounds also support different pathologies. Genetic studies on single nucleotide polymorphisms (SNPs) of PCV patients reported a high association of rs10490924 (A69S) variants of the age-related maculopathy susceptibility 2 (ARMS2) gene with type 1 rather than type 2 patients.14 This SNP is known as the risk allele in NV-AMD rather than PCV.15 Bessho et al16 reported an association of A69S variants with larger lesion size in PCV patients. Previous studies suggested that hypoxia may induce the expression of VEGF with different susceptibilities depending on genetic background.17 Type 1 PCV, which has a closer relationship with A69S variants, would show a greater response to a hypoxic environment, inducing the expression of VEGF and subsequent CNV formation, and may therefore show a better response to anti-VEGF therapy than type 2 PCV.
The response of type 1 PCV to anti-VEGF therapy was comparable to that of NV-AMD in previous studies. The VIEW 1 and VIEW 2 studies evaluating treatment effects of anti-VEGF therapy for patients with NV-AMD showed a gain of 4–8 Early Treatment Diabetic Retinopathy Study (ETDRS) using the same period as the current study and the 2q8 aflibercept regimen.18 Using the conversion proposed by Gregori et al,19 type 1 patients showed a gain of 18 and 13 approximate ETDRS letters at 3 and 6 months, respectively, in the current study. The superiority of the aflibercept response in our study is likely due to the different baseline visual acuities as well as the different subjects limited to PCV. A greater BCVA improvement in lower baseline visual acuity has previously been reported.20 ,21 The baseline visual acuity was 53.6 ETDRS letters in the VIEW study and 45 approximate ETDRS letters in our study. The results for the type 2 patients were comparable to those of previous studies with typical PCV. A retrospective review of aflibercept treatment for PCV22 showed that the mean BCVA improved by −0.10 and −0.14 logMAR scale at 3 and 6 months, respectively, which was similar to that of type 2 patients in our study (improvement of −0.08 and −0.10, respectively). A comparative study of anti-VEGF treatment effects between typical NV-AMD and PCV23 reported that the BCVA improvement in the NV-AMD was superior to that in the PCV (−0.22 vs −0.09 logMAR scale after 3 months; and −0.18 vs −0.07 logMAR scale after 6 months). In the current study, type 1 patients showed a greater BCVA improvement than type 2 patients (−0.34 vs −0.08 logMAR scale after 3 months; and −0.30 vs −0.10 logMAR scale after 6 months). Type 1 and type 2 patients therefore showed similar results to patients with NV-AMD and typical PCV, respectively, in their short-term responses to aflibercept.
Interestingly, the subfoveal CT of type 2 PCV showed greater reduction of aflibercept than that of type 1 PCV in the current study. This is likely due to the different choroidal vasculature between PCV subtypes. Similar to central serous chorioretinopathy (CSC), choroidal vascular hyperpermeability (CVH) and dilated choroidal vessels have been reported in patients with PCV.24 In addition, the thicker choroid is associated with CVH.25 Thus, the type 2 PCV with thicker subfoveal CT may have abnormally enlarged and permeable choroidal vessels. In contrast, type 1 PCV with thinner subfoveal CT appears to be associated with AMD in which reduced choroidal blood volume was exhibited.13 ,26 The suppression of CVH and vasoconstriction induced by aflibercept27 ,28 may be more prominent in type 2 PCV with greater vessel diameter, and may lead to greater reduction of subfoveal CT. A comparative study of subfoveal CT changes between PCV and typical NV-AMD after anti-VEGF treatment reported that patients with PCV showed thicker baseline subfoveal CT and greater reduction of subfoveal CT to aflibercept than patients with typical NV-AMD.29
This study had several limitations, including a small sample size, a short follow-up period and a lack of identifying genetic factor contribution between the two types of PCV. Because of low statistical power followed by small sample size, the greater improvement of largest PED height, largest polyp diameter, and dry macula ratio showed no significance between the two types of PCV, although they were almost twofold better in type 1 PCV than type 2 PCV. Although diagnosed definitely as PCV, several typical cases including PCV without BVN, and PCV with massive subretinal haemorrhage interfering with an ICGA interpretation were excluded. Thus, the current study may minimise the disease diversity. Despite these limitations, the treatment effects between subtypes of PCV were different. Our results suggest that consideration of angiographic features can be helpful in establishing a treatment strategy for patients with PCV. Further prospective studies with larger sample sizes and long-term follow-up periods are needed to confirm our results.
In summary, we classified PCV according to angiographic characteristics on ICGA. Type 1 and type 2 PCV showed distinct baseline features in the number of polyps, vascular leakage and choroidal thicknesses, suggesting different pathophysiology. Type 1 PCV resembling NV-AMD characterised by CNV showed superior short-term efficacy of intravitreal aflibercept compared with type 2 idiopathic PCV.
Design and conduct of the study (S.J., M.S.); collection and management of data (S.J.); analysis and interpretation of data (S.J., M.S.); and preparation, review, and approval of the manuscript (S.J., M.S.).
Funding This study was funded by the Yeungnam University Research Grant 2015.
Competing interests None declared.
Ethics approval Institutional Review Board of Yeungnam University Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All the data supporting our findings is contained within the manuscript.