We investigated the 12 month outcomes of IVR in Japanese AMD patients, and investigated whether the different phenotypes of exudative AMD influenced the visual outcomes of IVR. Our results demonstrated that IVR improved the mean BCVA of exudative AMD in the Japanese population, and the visual improvement was significantly greater in the tAMD subjects than in the PCV subjects. The phenotype of exudative AMD was a possible significant prognostic factor for the visual acuity after IVR.
Currently, IVR is the leading therapy for exudative AMD since the ANCHOR study demonstrated significantly better visual outcomes with monthly IVR than PDT in exudative AMD patients (most of them were likely tAMD patients) in Western countries [20, 21]. However, in Japanese exudative AMD, which likely includes a number of PCV patients, IVR may not show as good an outcome as in Caucasian subjects [8, 9, 22]. In the present study, the mean and median LogMAR visual acuity of all AMD were significantly improved by -0.09 and -0.12 logMAR units at 12 months post-initial IVR, respectively. This result was compatible to the SUSTAIN study  and a previous report , but lower than the PrONTO and CATT study. In addition, our results showed a significant increase in the mean BCVA in patients with tAMD, and a modest improvement in those with PCV. On the other hand, Song et al.  reported that IVR without PDT for PCV in Korean patients resulted in visual and anatomical significant improvements over a 1-year follow-up period.
PCV is known to have different characteristics as compared with tAMD, such as orange-red protrusions at the posterior pole of the retina and distinct forms of choroidal vascular abnormalities, including vascular networks of choroidal origin with polypoidal lesions at their border visualized by ICG [16, 18]. In addition, Nakashizuka et al.  suggested that the histopathologic characteristic of PCV was hyalinization of the choroidal vessels like arteriosclerosis, which is different from the CNV associated with tAMD. Since PCV accounts for 54.7% of patients with neovascular AMD in the Japanese population  and 22.3% in the Chinese population , it is important to determine if there are some differences in the efficacy of anti-VEGF therapy against PCV and tAMD to choose the correct intervention for neovascular AMD in Asian populations.
It was interesting that the PCV patients showed poorer improvements in their BCVA than tAMD patients, although both phenotypes showed similar and significant improvements in their CRT during the 12 months after the initial IVR. A previous report showed a decrease in macular edema after three monthly bevacizumab injections in PCV cases . Similarly, the macular edema evaluated by the CRT measurements was improved in four out of five eyes with PCV (80%) in the PEARL study. However, the improvement in the BCVA was less than that in the ANCHOR or MARINA trials, although the reasons are unknown . We hypothesized that there might be factors other than macular edema which influence the visual acuity in tAMD and PCV cases differently. Although the mean baseline GLD was significantly greater in the PCV group than in the tAMD group in the present study, the results of the multivariate logistic regression analysis revealed that the lesion phenotype (tAMD or PCV) was the independent prognostic factor for the 12 month visual outcome after IVR. Moreover, the ANOVA indicated a significantly better visual prognosis in tAMD than PCV treated by IVR over a 12 month follow-up period. The logistic regression analysis also determined higher BMI as an independent beneficial factor for visual improvement after IVR, although the reason was unknown. A recent study demonstrated that circulating VEGF-A levels were strongly correlated with BMI  and the patients with higher baseline VEGF-A levels might be more susceptible to ranibizumab treatment. In the present study, the mean number of IVR injections was 4.1 (3.9 in tAMD group, 4.2 in PCV group), which was compatible with previous reports [24, 31]. However, these reports and our results did not achieve an equivalent improvement in BCVA when compared to the ANCHOR or MARINA study. This suggests that some patients in our study might have been under-treated by the PRN protocol, as discussed in the SUSTAIN study . In addition, there might be an extended interval between a decision of retreatment and a performance of retreatment in our study. Delay of treatment might have a potential risk of irreversible VA deterioration , and may be associated with a lower number of retreatments with IVR.
The effects of IVR against PCV are currently contentious, and no consensus has been made to date. Some studies reported that the polypoidal lesions of PCV were barely resolved by anti-VEGF monotherapy, which might explain the limited efficacy of IVR against PCV [9, 10]. However, other reports suggested that the disappearance of the polypoidal lesions occurred at a high rate in PCV cases with anti-VEGF monotherapy [26, 33, 34]. Although the PCV cases showed a modest improvement in their mean BCVA over 12 months in the present study, our results demonstrated that IVR rescued the vision of PCV patients, since we previously reported that the mean BCVA of PCV cases had deteriorated significantly by 12 months following their natural course . In addition, some recent studies reported a significant improvement of the visual acuity of PCV patients using IVR [26, 33, 34]. A recent report demonstrated that several pretreatment factors of PCV influenced the outcome of IVR , which might cause the inconsistent results of those studies regarding the effect of IVR on PCV. The worse baseline BCVA in the tAMD group than the PCV group (though not significant) might be associated with the Ceiling effects on the BCVA change after the treatment in the present study . Further studies with prospective nature using larger and better matched populations will be required to make a robust conclusion. The lack of data about the duration of symptoms that may influence the outcome of the treatment is another limitation of the present study.
It is interesting that several reports have shown different outcomes for PDT between tAMD and PCV patients [38, 39]. In those reports, significantly better visual outcomes were demonstrated for PCV than tAMD. Recently, a multi-center study was conducted to compare the effects of PDT and IVR in patients with PCV, and reported that both therapies as well as their combination (PDT + IVR) resulted in improvements of the patients’ visual acuity at 6 months post-treatment . In addition, PDT monotherapy and combination therapy achieved a significantly higher proportion of patients with complete polyp regression at 6 months than IVR monotherapy. Hence, it is important to evaluate the long-term results of IVR with a large number of subjects to determine the efficacy and durability of this therapy, particularly in PCV patients. Taken together, further investigation will be needed to determine the correct indications for IVR for exudative AMD.