Therapeutic effects of ranibizumab in patients with polypoidal choroidal vasculopathy

Polypoidal choroidal vasculopathy (PCV) was first defined by Yannuzzi in 1982. It is characterized by the presence of orange-red polypoidal vascular lesions beneath the retinal pigment epithelium (RPE) that are usually associated with hemorrhagic or serous pigment epithelial detachment (PED) [1, 2]. The gold standard for PCV diagnosis is indocyanine green angiography (ICGA). It is defined as the presence of grape-like clusters of hyperfluorescence within the choroidal circulation within the first 6 min after the injection of indocyanine green dye, with or without an associated branching vascular network (BVN) [3]. PCV accounts for 10–54% of previously diagnosed age-related macular degeneration (AMD) cases in Asian populations [4, 5]. The presence of hemorrhagic or serous PED in PCV may lead to recurrent episodes of vitreal hemorrhage and exudative maculopathy, which may cause significant and permanent vision loss and therefore seriously affect quality of life [6].

Among the many treatment options, photodynamic therapy (PDT) has been proposed as a standard treatment, especially for lesions under the fovea. Studies have shown that PDT could lead to the complete regression of polyps in 73–99% of patients with stable visual acuity [7‐9]. However, for lesions with multiple, widespread polyps, PDT could damage normal tissue, and repeated PDT could cause subsequent hemorrhage. Recently, studies have shown that samples of aqueous humor and tissue from PCV patients show increased levels of vascular endothelial growth factor (VEGF) [10, 11]. This indicated another treatment modality that could be used for PCV – anti-VEGF agents. Theoretically, ranibizumab could lead to the resolution of subretinal hemorrhage and decrease in macular edema. To achieve synergistic treatment effects, PDT and anti-VEGF injections were combined. There are studies that report that combined therapy led to improved VA, a reduced subretinal hemorrhage rate and an increased lesion regression rate compared to PDT alone [12‐14]. However, the use of ranibizumab monotherapy to treat PCV has not been sufficiently explored. Two randomized clinical trials (EVEREST and LAPTOP) reported that ranibizumab was more effective in improving VA than PDT [14, 15]. Several studies have also reported the stabilization or even the improvement of vision in PCV patients who received anti-VEGF treatment alone [14‐20]. There is currently no consensus on the optimal treatment plan in terms of the use of combination therapy or anti-VEGF therapy for the initial treatment of PCV. The aim of our study is to report the efficacy of repeated injections of intravitreal ranibizumab with or without PDT for the treatment of PCV and to determine the possible factors predictive of visual outcomes.

Because of the rapid progress of medical science, physicians have developed a deeper understanding of the pathogenesis of PCV. This has led to the development of a variety of treatment modalities, yet at present there is no consensus on the optimal treatment plan for PCV. PDT was once proposed as a standard treatment modality and is the most widely discussed modality in the literature. Recent PDT monotherapy studies have reported favorable results, with more than half of patients reporting the stabilization or improvement of vision and a polyp regression rate of 80–95% [21‐25]. However, there are numerous disadvantages of PDT treatment, including its unsuitability for the treatment of multiple, widely-distributed lesions and its poor results for patients with substantial PED or submacular hemorrhage. Possible adverse events such as choroidal atrophy, massive subretinal or suprachoroidal hemorrhage and RPE tears after treatment also prevented its further use [26]. The latest development in PCV treatment was the use of anti-VEGF agents. Recent studies have found increased levels of VEGF in patients after PDT treatment, which may contribute to disease recurrence [27]. Various studies have found ranibizumab to be effective in reducing subretinal fluids and stabilizing or even improving visual acuity. Meanwhile, the complete regression of polyps was observed in only 14–40% of patients [12, 18, 28, 29]. This indicated that anti-VEGF therapy alone may have a relatively poor effect on the choroidal vascular branching network and polypoidal complexes. The EVEREST II study indicated that a combination therapy group had more improvement in VA and increased polyp regression rates compared to the ranibizumab monotherapy group at the 12-month follow-up [30]. Thus, physicians began to favor PDT and anti-VEGF combination therapy over PDT or anti-VEGF monotherapy alone. However, the current consensus for the treatment of PCV proposes that the ultimate objective is to stabilize visual acuity rather than reduce polyps. Therefore, more research data are needed to evaluate the visual outcomes of PCV patients initially treated with ranibizumab.

To observe the effect of intravitreal ranibizumab on treatment-naïve PCV, we enrolled 74 patients and collected data from 80 eyes, all of which received ranibizumab injections in a “3 + PRN” pattern. By the end of the study, 40/80 (50%) eyes had received more than 3 injections of only ranibizumab; 18/80 eyes (22.5%) were also subject to PDT treatment during follow-up. Our treatment strategy resulted in a statistically significant improvement in the BCVA and a reduction in CRT at the 3-month follow-up (p < 0.01). The mean BCVA improvement was 7.25 ± 12.44 letters, and the mean CRT reduction was 114.95 ± 237.21 μm. All eyes had stable vision, and none lost more than 15 letters in terms of VA. The short-term results of the intravitreal ranibizumab injections were satisfying; however, the 12-month follow-up results were less encouraging. There was still a significant reduction in CRT of 101.55 ± 256.07 μm (p < 0.01), but the mean BCVA was only slightly increased (3.40 ± 15.44 μm) and was not significantly different compared to baseline (p > 0.05). Two eyes (2.5%) suffered severe vision loss, one of which was due to choroidal atrophy after PDT treatment. Compared to the results of previous studies, the BCVA of the patients at the last follow-up did not improve significantly, although 78/80 eyes (97.5%) had stable vision [12, 28, 29, 31, 32]. This may be due to the retrospective nature of this study. Unlike randomized clinical trials, this study used a 3 + PRN treatment regimen, and the treatment decisions were based purely on the physician’s experience, which could result in under-treatment or delayed treatment and therefore lead to insignificant improvement in the BCVA at the end of the study. We believe that the visual results would have been improved if the retreatment criteria in clinical trials were followed in clinical practice. At the 12-month follow-up, the subretinal fluids in 43 eyes (60.6%) were mostly or completely absorbed, and PED in 39 eyes (55.7%) was resolved. The morphological changes shown during OCT were consistent with the results described by Kokame et al. [18]. Based on ICGA, 37 eyes (46.3%) had improvement in terms of polyps, but only 15 eyes (18.8%) showed complete regression (see Fig. 3b and Fig. 3d for examples of complete regression; see Fig. 4b and d for examples of recurrence). Of these 15 eyes, most had received PDT treatment after the 3 initial injections of ranibizumab, indicating that PDT played an important role in reducing polyps, although no significant differences were found in eyes that received ranibizumab monotherapy and PDT treatment in terms of BCVA, CRT, the reduction of subretinal fluids and PED. The EVEREST study showed that the combination therapy group had better VA and higher polyp regression rates compared to the ranibizumab monotherapy group [14, 30], while our study results demonstrated that ranibizumab given as an initial treatment could maintain VA in most PCV patients. Additional PDT treatment could improve polyp regression; however, no difference in VA was shown between the groups. The most recent study (PLANET study) with a large sample size, which compared anti-VEGF monotherapy and PDT rescue therapy, had similar results [20]. At the 12-month follow-up, more than 85% of patients treated with aflibercept monotherapy showed stabilized vision or functional improvement, and 40% of patients showed complete polyp regression. Of all the patients, 85% did not require PDT rescue treatment, indicating that aflibercept monotherapy could achieve VA stabilization.

In previous studies, there were discrepancies regarding the predictive factors of PCV visual outcomes. Possible predictive factors include age, gender, history of PDT, recurrence, baseline BCVA, baseline CRT, lesion size, lesion location, and the presence of characteristics such as grape-like polypoidal lesions, subretinal fluids, PED, CNV, lipid deposition and subretinal hemorrhage. Of these possible factors, decreased age, absence of a history of PDT, better baseline BCVA, smaller lesion size, and the absence of recurrence/PED/grape-like polypoidal lesions have been reported as independent factors correlated with better visual outcomes [31‐34]. By using simple linear regression and stepwise multivariate linear regression, our study identified baseline BCVA, subretinal fluids and the greatest lesion diameter as independent factors predictive of relatively improved VA at final follow-up. A better baseline BCVA indicates that the disease was relatively mild; therefore, a therapeutic effect was guaranteed with timely treatment. The greatest lesion diameter was also repeatedly mentioned as a predictive factor in previous studies. It is easily understood that larger lesions are usually accompanied by choroidal neovascularization, massive hemorrhage or severe scarring, which can severely damage visual acuity. Subretinal fluids were a factor we identified that has not been previously mentioned in the literature. We believe that this is because eyes with subretinal fluids generally respond better to anti-VEGF treatment.

Further research is needed to determine which patients benefit more from ranibizumab monotherapy and which patients require additional PDT treatment. Several studies reported that eyes with relatively good baseline BCVA obtained increased benefit from ranibizumab treatment [28, 32, 33]. Other possible predictive factors include lesion type, lesion size, subretinal hemorrhage size, the presence of PED at diagnosis and a history of PDT [31, 32]. In our study, patients who underwent additional PDT treatment were often found to have large polyps and increased PED.

The main limitations of our study were its retrospective, nonrandomized nature and its relatively small sample size. Lesions were not classified, and the decision to administer additional treatment was based purely on the physician’s experience. All of these factors could result in selection bias. In addition, not all patients underwent ICGA at the 3-month follow-up; therefore, polyp regression at the 12-month follow-up could possibly be the result of the natural course of disease. The follow-up period was also relatively short. PCV is a disease with possible recurrence; therefore, longer follow-up periods are required. Because of the age distribution in the PCV disease population, cataracts are a common condition in patients. Although significant changes in lens opacity were not observed during follow-up, enrolling patients both with and without cataract extraction in the study population is a potential source of heterogeneity.

Our findings demonstrated that three monthly injections of ranibizumab as an initial treatment could significantly improve VA in PCV patients in the short term. At 12 months postinjection, ranibizumab treatment could stabilize VA in most PCV patients. Patients who received additional PDT treatment had a significantly increased polyp regression rate. Further research is needed to determine the optimal type of patient who should receive ranibizumab monotherapy.