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Review Article

Anti-VEGF Therapy for Neovascular AMD and Polypoidal Choroidal Vasculopathy

Cheung, Gemmy Chui Ming FRCOphth*, †; Lai, Timothy Y.Y. MD, FRCS, FRCOphth; Gomi, Fumi MD§; Ruamviboonsuk, Paisan MD; Koh, Adrian MMED, FRCS; Lee, Won Ki MD, PhD*, *

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Asia-Pacific Journal of Ophthalmology: November 2017 - Volume 6 - Issue 6 - p 527-534
doi: 10.22608/APO.2017260
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Age-related macular degeneration (AMD) is a neurodegenerative eye disease and is a major cause of blindness in people aged 50 years or older. By 2040, global projected cases of AMD will be 288 million, with the largest number of cases in Asia (113 million).1-3 Since the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapy in the mid-2000s, the management of neovascular AMD has been revolutionized, leading to a much brighter outlook for patients afflicted with this condition. Anti-VEGF therapy is currently the standard of care for neovascular AMD. Registry data from several countries have reported a significant decrease in the incidence of AMD-associated blindness since the introduction of anti-VEGF therapy.4-6

There have been fewer studies on AMD in Asian populations. Nonetheless, the understanding of the epidemiology, risk factors, and genetic architecture of AMD in Asians has advanced significantly over the past 2 decades. Reports suggest that, despite some differences in clinical manifestation, Asian and white populations share many key risk factors.7 Regarding therapy, the efficacy and safety of anti-VEGF therapy in Asian patients with neovascular AMD is also less well investigated compared with white populations. In addition, polypoidal choroidal vasculopathy (PCV), generally believed to be a subtype of neovascular AMD, constitutes 50-60% of neovascular AMD cases in Asians (versus 10% in Western populations).2,8 The optimal treatment modality of PCV remains unclear. Recently, 2 major randomized trials have been presented that have provided new evidence on the optimal treatment for PCV. The aim of this review is to summarize the latest evidence on anti-VEGF therapy for neovascular AMD and PCV in Asians to help guide clinicians managing patients with this condition.


Pegaptanib (Macugen) was the first anti-VEGF agent approved for use in neovascular AMD.9 However, subsequent experience with ranibizumab (Lucentis), aflibercept (Eylea), and the off-label use of bevacizumab (Avastin) have demonstrated more favorable visual outcomes and have largely replaced pegaptanib in clinical use.10-13

Ranibizumab is a Fab fragment of humanized monoclonal antibody against VEGF-A. In the pivotal MARINA and ANCHOR studies, patients gained 7-11 letters over 12 months with monthly injections.10,11 Compared with previous standard of care [photodynamic therapy (PDT) or sham], treatment with ranibizumab resulted in a difference of 17 to 18 letters at month 12.10,11 The efficacy and safety of ranibizumab for neovascular AMD in the Asian population was initially evaluated in the phase 2/3 open-label, multicenter EXTEND studies (EXTEND I in Japanese patients, EXTEND II in Chinese patients, EXTEND III in South Korean and Taiwanese patients).14-16 All 3 studies demonstrated significant improvement in best corrected visual acuity (BCVA) from baseline (+9.3 to 12.7 letters), whereas very few patients lost 15 letters or more.14-16 Recently, the phase 4, randomized, double-masked, multicenter DRAGON study based in China further compared the efficacy of ranibizumab monthly versus pro-re-nata (PRN) regimen.17 Significant improvement in BCVA was achieved in both arms (+12.1 letters in the monthly arm, +9.4 in the PRN arm). Between month 12 and month 24, patients were treated with ranibizumab 0.5 mg PRN guided by visual acuity (VA) stabilization criteria. At month 24, the BCVA gain was largely maintained (+10.6 letters in the monthly arm, +8.7 letters in the PRN arm) with a mean of 4.5 to 4.7 additional injections.

Aflibercept is a fusion protein combining the ligand-binding domains of VEGFR1 and VEGFR2, which binds both VEGF and placental growth factor. The efficacy and safety of aflibercept was evaluated in the pivotal VIEW studies, which demonstrated that aflibercept given bimonthly after 3 initial loading doses was noninferior to ranibizumab 0.5 mg monthly and resulted in mean BCVA improvement of 8.4 letters from baseline.12,13 Importantly, the VIEW 2 study included 10.1-12.0% of participants with Asian ethnicity.12 A subgroup analysis in the Japanese subpopulation of the VIEW 2 study18 demonstrated that at week 52, all Japanese patients in the aflibercept groups (n = 70) avoided losing less than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, compared with 96% of Japanese patients (n = 23/24) treated with ranibizumab, and achieved a mean improvement in BCVA of 8-10 letters. The authors concluded that visual and anatomical outcomes were comparable between Japanese patients and the overall VIEW 2 population.

Conbercept is an anti-VEGF agent that consists of the fourth binding domain of VEGFR2 in addition to VEGF binding domains of VEGFR1 and VEGFR2.19 The additional binding domain is thought to decrease the positive charge of the molecule and result in decreased adhesion to the extracellular matrix. The AURORA study was a 12-month, randomized, double-masked, controlled-dose, interval-ranging phase 2 clinical trial conducted in China to assess the safety and efficacy of conbercept in patients with CNV secondary to AMD.20 The study demonstrated statistically significant functional and anatomic improvement after 3 initial doses, and these outcomes were maintained or improved further through month 12 following either monthly or PRN regimen. At month 12, mean changes in BCVA compared with baseline ranged from 9.31 letters (0.5 mg monthly) to 15.43 letters (2.0 mg monthly).

Although bevacizumab is not licensed for the treatment of neovascularization, its efficacy has been evaluated in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), which compared ranibizumab versus bevacizumab using monthly versus PRN dosing.10 The CATT study established that when used with the same dosing regimen, bevacizumab is noninferior to ranibizumab within the prespecified noninferiority margin. Two other randomized studies (IVAN and GEFAL) also concluded that ranibizumab and bevacizumab have similar efficacy in neovascular AMD.21,22


Although anti-VEGF therapy has been shown to be effective for both type 1 and type 2 neovascularization (occult and classic pattern leakage based on fluorescein angiography findings), the evidence for anti-VEGF to treat type 3 neovascularization [also known as retinal angiomatous proliferation (RAP)] is less robust.23 Retinal angiomatous proliferation is a unique variant of neovascular AMD and has been estimated to constitute up to 15% of neovascular AMD in white populations but is possibly less common in Asian populations. Clinical features distinctly in this subtype include the association with reticular pseudodrusen, thin choroid, and development of geographic atrophy (GA). Although anti-VEGF therapy is also frequently used in this subtype of neovascular AMD, most studies on RAP have been limited by the small number of subjects and variable follow-up duration. In addition, with advances in imaging that improve the accuracy of staging RAP lesions, it is now apparent that treatment response is highly dependent on the stage of lesion and no single treatment is equally effective in all stages. Many case series reported stabilization or improvement of visual acuity and reduced macular thickness in eyes with RAP after treatment with ranibizumab, aflibercept, and bevacizumab.24-29 Visual improvement was more common in eyes with stage 1 and 2.26,27,30 Presence of pigment epithelial detachment (PED) in stage 2 and stage 3 lesions is thought to be associated with worse prognosis.25,31 In a prospective study, Parodi32 reported that both ranibizumab and bevacizumab were effective in improving vision in eyes with stage 1 and 2 lesions, but resolution of PED was more common in the ranibizumab group compared with the bevacizumab group (90% vs 40%). In a recent meta-analysis of 190 eyes with stage 2 and 3 RAP, Tsai et al23 reported overall visual acuity improved by 6.5 letters at the final follow-up.


The role of VEGF in the pathogenesis of PCV is less clear compared with typical AMD. Evidence of VEGF expression in vascular endothelial and retinal pigment epithelial (RPE) cells in studies analyzing surgical specimens have been inconsistent.33-35 The concentration of VEGF in aqueous humor was found to be elevated in eyes with PCV compared with normal controls but to a much lesser extent compared with eyes with typical neovascular AMD.36,37 There is currently a wide spectrum of treatment options for PCV, including focal laser photocoagulation; verteporfin PDT; anti-VEGF therapy with aflibercept, ranibizumab, and bevacizumab; and various combinations of these therapies.

In most of the pivotal studies of anti-VEGF in neovascular AMD, indocyanine green angiography (ICGA) was not performed and patients with PCV were not specifically differentiated. Thus in most countries, there is no separate label under PCV, and patients may receive the same treatment as those with typical neovascular AMD. Early studies reported both ranibizumab and bevacizumab resulted in temporary stabilization of vision and reduction in exudation in PCV, with limited effect on polypoidal lesions or choroidal vascular changes.38,39 Subsequent studies with more patients and longer follow-up reported 17% to 40% of patients achieved 15 letters or more improvement in BCVA.40-43 Most of these studies used a regimen of monthly injections for 3 months, followed by PRN over 12 months (mean number of injections ranged from 4.2 to 6.1). Polypoidal lesion regression rate of up to 40% was reported at 12 months, although abnormal choroidal vascular complexes do not seem to be affected by anti-VEGF monotherapy.44

The PEARL studies consisted of 2 open-label studies in PCV using monthly ranibizumab (0.5 mg for 12 months in PEARL 1; 2.0 mg for 6 months in PEARL 2). The proportion of patients who gained 15 letters or more was 23% and 26% in the PEARL 1 and PEARL 2 studies, respectively.45 None of the patients lost 15 letters or more in visual acuity in either study. Visual acuity improvement was accompanied by anatomical improvement in reduction of subretinal hemorrhage and fluid in the majority of eyes, and decrease in polypoidal lesions was noted in 38% and 79% in the PEARL 1 and PEARL 2 studies, respectively.

The effect of ranibizumab was subsequently evaluated as 1 of the treatment arms in 2 multicenter randomized controlled trials. The EVEREST study compared the efficacy of PDT with or without ranibizumab 0.5 mg and ranibizumab monotherapy in achieving polyp closure based on ICGA. Although vision improved in all 3 arms (7.5 to 10.9 letters) at month 6, polyp closure rate was significantly lower in the ranibizumab monotherapy group (28.6%) compared with the PDT monotherapy group (71.4%; P < 0.01) and the PDT with ranibizumab group (77.8%; P < 0.01).46 The LAPTOP study is a phase 4, prospective multicenter randomized trial comparing the effect of PDT and intravitreal ranibizumab in PCV using a PRN retreatment regimen.43 At month 12, more patients in the ranibizumab arm had a VA gain of at least 0.2 logarithm of the minimum angle of resolution (logMAR) compared with the PDT arm (31% vs 17%; P = 0.039).44 At month 24, it was confirmed that injections of ranibizumab achieved better visual outcomes than PDT (P = 0.004). In addition, it was noted that although several patients in the PDT arm showed improvement in vision, approximately 15% of patients showed more than 6 lines of vision loss.43 Polyp closure rate was not assessed.

Several case series have also evaluated the efficacy of aflibercept following neovascular AMD posology in PCV and reported favorable visual outcome (VA gain of 5.5 to 10.5 letters) and polyp regression rate up to 69.2% at month 12.28,47-50 The EPIC study is a prospective, open-label study of intravitreal aflibercept in 21 eyes with PCV. The study reported stabilization of vision at 6 months (median vision was 20/40) and resolution of subretinal fluid (72%), subretinal hemorrhage (75%), regression of polyps (67%), and improvement of PED (87%).51 Inoue et al52 compared the functional and morphologic outcomes of patients treated using fixed bimonthly dosing versus PRN after 3 initial monthly doses and reported significant improvement in both groups. A post-hoc analysis of 29 Japanese patients with PCV (33% of 88 Japanese patients with PCV confirmed on ICGA) in the VIEW 2 study reported that no significant difference in visual acuity or retinal thickness reduction was noted between PCV and non-PCV groups treated with aflibercept. However, no posttreatment ICGA was available to determine angiographic outcome.53

There have been fewer studies reporting the results of bevacizumab for PCV. Favorable outcome in improving vision and macular exudation but limited polyp regression has been reported.38,54-56 Cho et al56 compared ranibizumab and bevacizumab monotherapy and reported no difference in polypoidal lesion regression rate, central macular thickness, and visual acuity at 6 months.

A subgroup analysis of 52 patients with PCV in the AURORA study who received intravitreal injections of conbercept reported significant visual acuity improvement of 14 letters at month 12, accompanied by complete regression of polyps in 52.9% to 56.5%.57

Recently, the outcomes of 2 large randomized controlled trials (EVEREST II and PLANET) evaluating anti-VEGF and combination therapy have been reported. At 1 year, significant visual acuity improvement was seen in eyes treated with ranibizumab monotherapy (+5.1 letters in EVEREST) and aflibercept monotherapy (+10.8 letters in PLANET). This was accompanied by polyp closure rates of 34.7% and 38.9% (ranibizumab monotherapy arm in EVEREST II and aflibercept monotherapy arm in PLANET, respectively). The mean number of injections in the monotherapy arms was 7.3 (EVEREST II, PRN after 3 initial monthly doses) and 8.1 (PLANET, fixed bimonthly dosing after 3 initial monthly doses).58,59 These results were further corroborated by the subgroup analysis of the DRAGON study in which 41.7% of the 334 enrolled patients were diagnosed with PCV based on ICGA.17 Significant improvement in BCVA was achieved in both PCV and non-PCV patients in the monthly arm (+12.7 vs 12.1 letters) and the PRN arm (9.4 vs 9.4 letters) at 12 months.

Based on these clinical trial data, monotherapy with either ranibizumab or aflibercept can achieve visual improvement and reduction in disease activity and can be considered as first-line treatment in patients with PCV. There are no head-to-head studies to provide direct comparison among anti-VEGF agents. Comparison across studies should be interpreted with caution in view of potential differences in baseline characteristics, particularly BCVA, along with differences in dosing regimens.


Combination therapy (anti-VEGF with PDT) was evaluated in the MONT BLANC and DENALI studies. In the MONT BLANC study, combination therapy was noninferior to ranibizumab monotherapy with regard to mean BCVA change at month 12 compared with baseline (2.5 vs 4.4 letters). However, no benefit in terms of reducing the number of ranibizumab injections over 12 months was demonstrated from the combination treatment. The DENALI trial investigated whether standard fluence PDT (SF-PDT) or reduced fluence PDT (RF-PDT) in combination with ranibizumab, followed by retreatment with ranibizumab as needed, was noninferior to fixed monthly ranibizumab injections.60 Mean vision improvement at month 12 was +5.3 and +4.4 letters with SD-PDT and RF-PDT, compared with +8.1 letters with ranibizumab monotherapy. However, noninferiority of combination regimens to ranibizumab monotherapy was not demonstrated. Based on these results, combination therapy is now rarely used for the treatment of typical neovascular AMD.


The rationale for combining anti-VEGF with PDT in RAP is based on the proposed additional occlusive action on the retinalretinal anastomosis and retinal choroidal anastomoses.30,61 Several small case series using the combination of ranibizumab or bevacizumab with PDT in RAP have reported good visual and anatomical outcomes.62-64 Saito and colleagues65 reported encouraging results with a combination of PDT and bevacizumab in 11 eyes with stage 2 to 3 RAP, in which visual acuity improvement was accompanied by reduction in macular thickness and resolution of angiographic leakage in all study eyes. In a separate study, visual acuity improvement was maintained at 2 years after PDT and 3 monthly ranibizumab injections in eyes with RAP of all stages.66 In a study with 3 years of follow-up, Rouvas and colleagues67 compared the treatment effect of ranibizumab alone with PDT and ranibizumab with PDT and intravitreal triamcinolone (IVTA) in eyes with RAP of all stages. Surprisingly, visual acuity improvement was only seen in the group treated with PDT and IVTA, although the group treated with PDT and ranibizumab had the best anatomical outcome. However, more patients who received IVTA underwent cataract surgery, which may have been an important confounding factor.


For extrafoveal PCV, focal laser with or without anti-VEGF remains a viable treatment option. Combining anti-VEGF with focal laser can further resolve subfoveal exudation more rapidly, leading to more rapid visual improvement. Combination therapy including PDT and anti-VEGF therapy has also been reported to achieve significantly better visual outcomes than PDT alone and reduce the rate of PDT-related hemorrhages.68-72 Furthermore, combination therapy has been shown to achieve high rates of polyp closure,2,46 which has traditionally been considered an important endpoint for the treatment of PCV, as achieving this angiographic endpoint may significantly reduce the need for continued anti-VEGF treatments.

In the EVEREST I study, the combination therapy arm achieved a significantly higher polyp closure rate compared with ranibizumab monotherapy (77.8% vs 28.6%; P < 0.01). Although the study was not powered to evaluate differences in vision change, patients in the combination arm also achieved the highest BCVA gain numerically (10.9 letters) compared with patients in the ranibizumab monotherapy arm (9.2 letters) or the PDT monotherapy arm (7.5 letters) at month 6. In the EVEREST II study, the combination arm achieved superior BCVA gain (8.3 vs 5.1 letters; P = 0.013), along with superior anatomical outcome, including higher polyp closure rate (69.3% vs 34.7%; P < 0.01) and higher proportion with absence of disease activity (79.5% vs 50.0%) at month 12 compared with ranibizumab monotherapy. The combination arm also required fewer injections (mean 5.2 vs 7.3 injections over 12 months), with 50.6% of patients in the combination arm requiring only 3-4 injections over 12 months, which was significantly lower than that in the monotherapy arm (26.2%). However, currently there are no clear criteria to identify this subgroup at baseline. These results suggest that although ranibizumab monotherapy is safe and achieves moderate BCVA gains in PCV, combination therapy is superior in terms of BCVA gain and polyp closure and can also reduce the number of ranibizumab injections required in the first year of treatment.58

In addition to combination therapy performed at baseline, deferred combination has been evaluated in the Fujisan study.73 Patients randomized to the deferred PDT arm were evaluated after 3 monthly intravitreal ranibizumab injections, and deferred combination treatment was performed in those who met the retreatment criteria. At 1 year, similar BCVA and polyp closure outcomes were reported in the 2 arms. With this approach, more than half of the patients in the deferred arm (17 out of 31 patients) avoided PDT, although more injections (3.8 vs 1.5 in addition to 3 loading doses) were required.

The PLANET study evaluated deferred rescue PDT combination therapy. After 3 initial monthly aflibercept injections, all patients were treated with fixed 8 weekly aflibercept to month 12. In addition, patients were evaluated for rescue criteria, which included 1) BCVA less than or equal to 73 ETDRS letters; 2) presence of new or persistent fluid on optical coherence tomography; 3) evidence of active polyps on ICGA; and either 4) BCVA loss, no change, or insufficient gain (<5 letters gain); or 5) BCVA gain more than 5 letters but less than 10 letters and investigator determines that PDT would be of benefit. The study found that a large majority of patients did not meet the rescue criteria after 3 initial monthly aflibercept injections (87.9% and 85.7% in the aflibercept monotherapy arm and combination arm, respectively; P = 0.84) and only less than 15% of patients randomized to the rescue PDT arm received active rescue PDT. Both treatment arms achieved similar BCVA gain (10.7 vs 10.9 letters) and polyp regression rates (38.9% vs 44.8%, respectively; P = 0.32). Over 80% of patients had no signs of polyp activity at week 52. Patients who met the rescue criteria had worse visual outcome regardless of rescue PDT (+4.2 in the rescue PDT arm vs +1.9 letters in the sham PDT arm; P = 0.89). Polyp closure rate in patients who received active rescue PDT (44.4%) was similar to that in patients who did not meet rescue criteria (43.2-44.8%). The PLANET study thus concluded that no significant additional benefit was demonstrated in patients receiving fixed dosing aflibercept at week 52 by adding rescue PDT.59


Despite the favorable initial results with anti-VEGF up to 2 years, studies with longer follow-up have highlighted that the long-term visual outcome may be less favorable. The SEVEN UP study followed up a subgroup of patients enrolled in ANCHOR, MARINA, and HORIZON trials and found that the mean BVCA decreased to -8.6 letters worse than baseline after 7 years.74 Most patients did not attain durable treatment-free cessation of exudative AMD 7-8 years after intensive anti-VEGF therapy for 2 years, suggesting that treatment may need to be continued for many years. Similarly, in the 5-year follow-up of the CATT study, most of the visual gain at 2 years was lost (mean change in VA was -3 letters from baseline and -11 letters from 2 years).75 The mean number of treatments after the clinical trial ended was 15.4. In a separate report using the Fight Retinal Blindness database, after a mean follow-up time of 53.5 months, better long-term outcomes were reported, which the authors postulated to be the result of more injections given in years 3-5.76

Development of macular atrophy (MA) has been noted in a significant proportion of patients after anti-VEGF therapy. In the SEVEN UP study, 98% of subjects showed RPE atrophy. In follow-up reports of the CATT and IVAN studies, development of MA was associated with poorer visual outcome.21,77 There are few studies in Asian subjects that report long-term functional or anatomical outcome beyond 2 years. Kuroda et al78 reported the incidence of RPE atrophy progression in Japanese patients treated with ranibizumab of 3.8% at 12 months, increasing to 5.4% after 26.7 months. These figures seem to be lower than those reported in the white population. The authors further reported the incidence of RPE atrophy was lower in PCV than in typical AMD, and the rate of progression was also slower in PCV.

Eyes with RAP are thought to have a high risk of development of MA. McBain and colleagues79 reported an incidence of de novo development of MA of 86% after anti-VEGF treatment in eyes with RAP. High incidence of development of MA has also been reported in Asian populations. Inoue and colleagues80 reported that after 3 years of treatment with ranibizumab, 11 of 17 eyes with RAP developed macular atrophy. In Korean patients with RAP followed up for 2 years, MA had developed in 37.2% (16/43 eyes).81 Subfoveal choroidal thinning at baseline, the presence of reticular pseudodrusen, and the presence of GA in the fellow eye at baseline were associated with increased risk of GA development after treatment. Although these data suggest there may be ethnic differences in the progression of RPE atrophy after treatment, further studies are needed to confirm long-term morphological outcome in Asians. Furthermore, as atrophy is a wellrecognized part of the natural history of RAP, it is not known whether anti-VEGF therapy has a causal effect.

Retinal pigment epithelium tear is a complication of neovascular AMD and PCV and may adversely affect visual outcome. The risk of RPE tear associated with large PED (such as in PCV and RAP) is well recognized and may represent the natural history of PED. Therefore, it remains unclear whether anti-VEGF therapy increases the risk of RPE tear in eyes with PCV or RAP.

The systemic safety profile of intravitreal anti-VEGF therapy continues to be a potential area of concern, although the landmark trials in ranibizumab and aflibercept delivered as intravitreal injection did not show a significant increase in stroke risk or antiplatelet trialist collaboration events.11,13,82,83 In patients who receive intravenous bevacizumab as part of cancer treatment, an increased risk of arterial and venous thromboembolism and hypertension has been reported. In the CATT study, the bevacizumab group had a higher risk of serious systemic adverse events than the ranibizumab group. In the IVAN study, mortality was higher in groups treated with discontinuous ranibizumab or bevacizumab compared with groups treated continuously.10,21,84 Despite the small volume delivered intravitreally, differences in systemic exposure and reduction in plasma free VEGF have been noted, with the reduction in free VEGF levels greatest with aflibercept and least with ranibizumab.85,86 Associations between anti-VEGF exposure and risks of stroke and mortality have been inconsistently reported.87-90 Furthermore, it remains unclear whether patients with a history of stroke and heart attack are at higher risk when exposed to anti-VEGF therapy. A pooled analysis of 5 randomized controlled trials using ranibizumab seems to suggest that patients with a history of stroke may be at higher risk of developing stroke after anti-VEGF therapy. Therefore, it remains unclear whether anti-VEGF treatment should be modified for patients with a high risk of cardiovascular disease. A long-term postmarketing surveillance program is in place for ranibizumab and is likely to start soon for aflibercept. The need for heightened surveillance for systemic adverse events in patients treated with intraocular anti-VEGF cannot be over-emphasized.


The most important goal of treatment of neovascular AMD, including RAP and PCV subtypes, should be achieving the best possible visual outcome while minimizing the treatment burden. In neovascular AMD, anti-VEGF monotherapy is clearly the first line of therapy. Although monthly injection has been shown to produce the best visual outcome, intensive retreatment may not be sustainable in the long term. Other strategies to minimize treatment while maintaining visual gain include the use of the treat-and-extend strategy. Since its first description, its efficacy and safety has been demonstrated in large clinical trials91,92 and may represent a viable option in the Asia-Pacific region where frequent retreatment remains a major barrier.

For PCV, current evidence suggests that anti-VEGF monotherapy and combination therapy give excellent functional visual outcomes at 1 year and are acceptable initial treatment options. Advantages of anti-VEGF monotherapy include the independence from access to ICGA and PDT. In addition to the fixed dosing and PRN with monthly monitoring regimens evaluated in PLANET and EVEREST II, respectively, the role of a treat-and-extend regimen in PCV should also be further evaluated.93 In contrast, initial combination therapy has the advantage of reducing the need for retreatment with ranibizumab up to 1 year based on results from EVEREST II. However, rescue PDT may have additional benefit if aflibercept is used as monotherapy. Although focal laser therapy has largely been superseded by newer therapeutic options, this remains a useful therapeutic option for extrafoveal polyps. Combination with anti-VEGF therapy has been described to be effective in eyes with extrafoveal PCV in which exudation or hemorrhage extends to the fovea.94 Combination with anti-VEGF and/or selective PDT has been described to be effective in recurrent PCV.95

Despite the advances in various management approaches in neovascular AMD and PCV, there remain significant gaps in our knowledge of this disease. The pathogenesis of AMD, in particular the PCV subtype, remains to be explored. Improvement in understanding of VEGF independent pathways may lead to the development of novel therapeutic targets. The role of VEGF in nonneovascular forms of AMD, in particular in the maintenance of the choriocapillaris and implications in development of macular atrophy, is another area where further understanding is needed. A key gap in our understanding of optimal management for PCV is the importance of polyp closure. Despite the higher polyp closure rate of combination therapy, there is limited current evidence showing that this is directly related to visual outcome. Studies with extended follow-up are needed to evaluate whether higher polyp closure rates eventually may translate into better visual outcome or lower recurrences. Both the EVEREST II and the Fujisan studies demonstrated heterogeneity in response to initial therapy within the first 3 months. However, descriptions of predictive biomarkers such as choroidal thickness and choroidal vascular hyperpermeability have been limited to small clinical case series.96,97 Future clinical trials will be needed to address each of these knowledge gaps.


1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106-e116.
2. Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians. Prog Retin Eye Res. 2016;53:107-139.
3. Wong CW, Wong TY, Cheung CM. Polypoidal choroidal vasculopathy in Asians. J Clin Med. 2015;4:782-821.
4. Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular degeneration in Denmark: year 2000 to 2010. Am J Ophthalmol. 2012;153:209-213.e202.
5. Skaat A, Chetrit A, Belkin M, et al. Time trends in the incidence and causes of blindness in Israel. Am J Ophthalmol. 2012;153:214-221.e211.
6. Sloan FA, Hanrahan BW. The effects of technological advances on outcomes for elderly persons with exudative age-related macular degeneration. JAMA Ophthalmol. 2014;132:456-463.
7. Lim LS, Cheung CM, Wong TY. Asian age-related macular degeneration: current concepts and gaps in knowledge. Asia Pac J Ophthalmol (Phila). 2013;2:32-41.
8. Cheung CM, Li X, Mathur R, et al. A prospective study of treatment patterns and 1-year outcome of Asian age-related macular degeneration and polypoidal choroidal vasculopathy. PloS One. 2014;9:e101057.
9. VISION Clinical Trial Group, Chakravarthy U, Adamis AP, et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006;113:1508.e1501-e1525.
10. Group CR, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
11. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
12. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119: 2537-2548.
13. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121:193-201.
14. Tano Y, Ohji M, Group EXTEND-I Study Group. EXTEND-I: safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Acta Ophthalmol. 2010;88:309-316.
15. Zhao J, Li X, Tang S, et al. EXTEND II: an open-label phase III multicentre study to evaluate efficacy and safety of ranibizumab in Chinese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. BioDrugs. 2014;28:527-536.
16. Lee FL, Kwon OW, Chung H, et al. Ranibizumab in South Korean and Taiwanese patients with age-related macular degeneration: primary outcome of the EXTEND III study. Acta Ophthalmol. 2012;90:e406-e407.
17. Li X. Ranibizumab 0.5 mg in patients with polypoidal choroidal vasculopathy: results from the DRAGON Study. Poster presented at: American Academy of Ophthalmology Annual Meeting; October 15-18, 2016; Chicago, IL.
18. Ogura Y, Terasaki H, Gomi F, et al. Efficacy and safety of intravitreal aflibercept injection in wet age-related macular degeneration: outcomes in the Japanese subgroup of the VIEW 2 study. Br J Ophthalmol. 2015;99:92-97.
19. Wang Q, Li T, Wu Z, et al. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable antiangiogenesis effect in vivo. PloS One. 2013;8:e70544.
20. Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology. 2014;121:1740-1747.
21. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382:1258-1267.
22. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120:2300-2309.
23. Tsai ASH, Cheung N, Gan ATL, et al. Retinal angiomatous proliferation. Surv Ophthalmol. 2017;62:462-492.
24. Hemeida TS, Keane PA, Dustin L, et al. Long-term visual and anatomical outcomes following anti-VEGF monotherapy for retinal angiomatous proliferation. Br J Ophthalmol. 2010;94:701-705.
25. Shin JY, Yu HG. Optical coherence tomography-based ranibizumab monotherapy for retinal angiomatous proliferation in Korean patients. Retina. 2014;34:2359-2366.
26. Costagliola C, Romano MR, dell’Omo R, et al. Intravitreal bevacizumab for the treatment of retinal angiomatous proliferation. Am J Ophthalmol. 2007;144:449-451.
27. Gharbiya M, Allievi F, Recupero V, et al. Intravitreal bevacizumab as primary treatment for retinal angiomatous proliferation: twelve-month results. Retina. 2009;29:740-749.
28. Oishi A, Tsujikawa A, Yamashiro K, et al. One-year result of aflibercept treatment on age-related macular degeneration and predictive factors for visual outcome. Am J Ophthalmol. 2015;159:853-860.e851.
29. Tsaousis KT, Konidaris VE, Banerjee S, et al. Intravitreal aflibercept treatment of retinal angiomatous proliferation: a pilot study and short-term efficacy. Graefes Arch Clin Exp Ophthalmol. 2015;253:663-665.
30. Montero JA, Fernandez MI, Gomez-Ulla F, et al. Efficacy of intravitreal bevacizumab to treat retinal angiomatous proliferation stage II and III. Eur J Ophthalmol. 2009;19:448-451.
31. Reche-Frutos J, Calvo-Gonzalez C, Perez-Trigo S, et al. Ranibizumab in retinal angiomatous proliferation (RAP): influence of RAP stage on visual outcome. Eur J Ophthalmol. 2011;21:783-788.
32. Parodi MB, Iacono P, Menchini F, et al. Intravitreal bevacizumab versus ranibizumab for the treatment of retinal angiomatous proliferation. Acta Ophthalmol. 2013;91:267-273.
33. Matsuoka M, Ogata N, Otsuji T, et al. Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular membranes and polypoidal choroidal vasculopathy. Br J Ophthalmol. 2004;88:809-815.
34. Terasaki H, Miyake Y, Suzuki T, et al. Polypoidal choroidal vasculopathy treated with macular translocation: clinical pathological correlation. Br J Ophthalmol. 2002;86:321-327.
35. Nakashizuka H, Mitsumata M, Okisaka S, et al. Clinicopathologic findings in polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2008;49:4729-4737.
36. Lee MY, Lee WK, Baek J, et al. Photodynamic therapy versus combination therapy in polypoidal choroidal vasculopathy: changes of aqueous vascular endothelial growth factor. Am J Ophthalmol. 2013;156:343-348.
37. Tong JP, Chan WM, Liu DT, et al. Aqueous humor levels of vascular endothelial growth factor and pigment epithelium-derived factor in polypoidal choroidal vasculopathy and choroidal neovascularization. Am J Ophthalmol. 2006;141:456-462.
38. Gomi F, Sawa M, Sakaguchi H, et al. Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008;92:70-73.
39. Lai TY, Lee GK, Luk FO, et al. Intravitreal ranibizumab with or without photodynamic therapy for the treatment of symptomatic polypoidal choroidal vasculopathy. Retina. 2011;31:1581-1588.
40. Hikichi T, Kitamei H, Shioya S. Prognostic factors of 2-year outcomes of ranibizumab therapy for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2014;99:817-822.
41. Kang HM, Koh HJ. Long-term visual outcome and prognostic factors after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;156:652-660.
42. Ogino K, Tsujikawa A, Yamashiro K, et al. Intravitreal injection of ranibizumab for recovery of macular function in eyes with subfoveal polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2013;54:3771-3779.
43. Oishi A, Miyamoto N, Mandai M, et al. LAPTOP study: a 24-month trial of verteporfin versus ranibizumab for polypoidal choroidal vasculopathy. Ophthalmology. 2014;121:1151-1152.
44. Oishi A, Kojima H, Mandai M, et al. Comparison of the effect of ranibizumab and verteporfin for polypoidal choroidal vasculopathy: 12-month LAPTOP study results. Am J Ophthalmol. 2013;156:644-651.
45. Kokame GT, Yeung L, Teramoto K, et al. Polypoidal choroidal vasculopathy exudation and hemorrhage: results of monthly ranibizumab therapy at one year. Ophthalmologica. 2014;231:94-102.
46. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32:1453-1464.
47. Saito M, Kano M, Itagaki K, et al. Efficacy of intravitreal aflibercept in Japanese patients with exudative age-related macular degeneration. Jpn J Ophthalmol. 2017;61:74-83.
48. Yamamoto A, Okada AA, Kano M, et al. One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy. Ophthalmology. 2015; 122:1866-1872.
49. Hosokawa M, Morizane Y, Hirano M, et al. One-year outcomes of a treat-and-extend regimen of intravitreal aflibercept for polypoidal choroidal vasculopathy. Jpn J Ophthalmol. 2017;61:150-158.
50. Lee JE, Shin JP, Kim HW, et al. Efficacy of fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy: 1-year results of the VAULT study. Graefes Arch Clin Exp Ophthalmol. 2017;255:493-502.
51. Kokame GT, Lai JC, Wee R, et al. Prospective clinical trial of intravitreal aflibercept treatment for polypoIdal choroidal vasculopathy with hemorrhage or exudation (EPIC study): 6 month results. BMC Ophthalmol. 2016;16:127.
52. Inoue M, Yamane S, Taoka R, et al. Aflibercept for polypoidal choroidal vasculopathy: as needed versus fixed interval dosing. Retina. 2016;36:1527-1534.
53. Ogura Y. VIEW 2 study PCV subanalysis - effect of EYLEA on polypoidal choroidal vasculopathy (PCV) - ICGA subanalysis. Paper presented at: 53rd Annual Meeting of the Japanese Retina and Vitreous Society; November 28-30 2014; Osaka, Japan.
54. Lai TY, Chan WM, Liu DT, et al. Intravitreal bevacizumab (Avastin) with or without photodynamic therapy for the treatment of polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008;92:661-666.
55. Cheng CK, Peng CH, Chang CK, et al. One-year outcomes of intravitreal bevacizumab (Avastin) therapy for polypoidal choroidal vasculopathy. Retina. 2011;31:846-856.
56. Cho HJ, Baek JS, Lee DW, et al. Short-term effectiveness of intravitreal bevacizumab vs. ranibizumab injections for patients with polypoidal choroidal vasculopathy. Kor J Ophthalmol. 2012;26:157-162.
57. Qu J, Cheng Y, Li X, et al; AURORA Study Group. Efficacy of intravitreal injection of conbercept in polypoidal choroidal vasculopathy: subgroup analysis of the Aurora study. Retina. 2016;36:926-937.
58. Koh A. Ranibizumab and vPDT combination therapy versus ranibizumab monotherapy for macular PCV: 12-month results from the EVEREST II study. Paper presented at: American Academy of Ophthalmology Annual Meeting Subspecialty Day; October 14, 2016; Chicago, IL.
59. Iida T. Results of the PLANET study. Paper presented at: 10th Asia-Pacific Vitreo-retina Society Congress; December 9, 2016; Bangkok, Thailand.
60. Kaiser PK, Boyer DS, Cruess AF, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelvemonth results of the DENALI study. Ophthalmology. 2012;119:1001-1010.
61. Saito M, Iida T, Kano M, et al. Angiographic results of retinal-retinal anastomosis and retinal-choroidal anastomosis after treatments in eyes with retinal angiomatous proliferation. Clin Ophthalmol. 2012;6:1385-1391.
62. Lee MY, Kim KS, Lee WK. Combination therapy of ranibizumab and photodynamic therapy for retinal angiomatous proliferation with serous pigment epithelial detachment in Korean patients: twelve-month results. Retina. 2011;31:65-73.
63. Saito M, Iida T, Kano M. Combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol. 2012;153:504-514.e501.
64. Saito M, Iida T, Kano M. Two-year results of combined intravitreal anti-VEGF agents and photodynamic therapy for retinal angiomatous proliferation. Jpn J Ophthalmol. 2013;57:211-220.
65. Saito M, Shiragami C, Shiraga F, et al. Combined intravitreal bevacizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol. 2008;146:935-941.e931.
66. Saito M, Iida T, Kano M, et al. Two-year results of combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. Jpn J Ophthalmol. 2016;60:42-50.
67. Rouvas AA, Chatziralli IP, Theodossiadis PG, et al. Long-term results of intravitreal ranibizumab, intravitreal ranibizumab with photodynamic therapy, and intravitreal triamcinolone with photodynamic therapy for the treatment of retinal angiomatous proliferation. Retina. 2012;32:1181-1189.
68. Gomi F, Sawa M, Wakabayashi T, et al. Efficacy of intravitreal bevacizumab combined with photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2010;150:48-54.e41.
69. Sato T, Kishi S, Matsumoto H, et al. Comparisons of outcomes with different intervals between adjunctive ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;156:95-105.e101.
70. Tomita K, Tsujikawa A, Yamashiro K, et al. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy combined with intravitreal injections of ranibizumab. Am J Ophthalmol. 2012;153:68-80.e61.
71. Wong CW, Cheung CM, Mathur R, et al. Three-year results of polypoidal choroidal vasculopathy threated with photodynamic therapy: retrospective study and systematic review. Retina. 2015;35:1577-1593.
72. Yamashita A, Shiraga F, Shiragami C, et al. Two-year results of reducedfluence photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;155:96-102.e101.
73. Gomi F, Oshima Y, Mori R, et al. Initial versus delayed photodynamic therapy in combination with ranibizumab for treatment of polypoidal choroidal vasculopathy: the Fujisan Study. Retina. 2015;35:1569-1576.
74. Rofagha S, Bhisitkul RB, Boyer DS, et al; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120:2292-2299.
75. Comparison of Age-related Macular Degeneration Treatments Trials Research Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular agerelated macular degeneration: the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123:1751-1761.
76. Gillies MC, Campain A, Barthelmes D, et al. Long-term outcomes of treatment of neovascular age-related macular degeneration: data from an observational study. Ophthalmology. 2015;122:1837-1845.
77. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2014;121:150-161.
78. Kuroda Y, Yamashiro K, Tsujikawa A, et al. Retinal pigment epithelial atrophy in neovascular age-related macular degeneration after ranibizumab treatment. Am J Ophthalmol. 2016;161:94-103.e101.
79. McBain VA, Kumari R, Townend J, et al. Geographic atrophy in retinal angiomatous proliferation. Retina. 2011;31:1043-1052.
80. Inoue M, Arakawa A, Yamane S, et al. Long-term results of intravitreal ranibizumab for the treatment of retinal angiomatous proliferation and utility of an advanced RPE analysis performed using spectral-domain optical coherence tomography. Br J Ophthalmol. 2014;98:956-960.
81. Cho HJ, Yoo SG, Kim HS, et al. Risk factors for geographic atrophy after intravitreal ranibizumab injections for retinal angiomatous proliferation. Am J Ophthalmol. 2015;159:285-292.e281.
82. Cheung CM, Wong TY. Is age-related macular degeneration a manifestation of systemic disease? New prospects for early intervention and treatment. J Intern Med. 2014;276:140-153.
83. Lim LS, Cheung CM, Mitchell P, et al. Emerging evidence concerning systemic safety of anti-VEGF agents—should ophthalmologists be concerned? Am J Ophthalmol. 2011;152:329-331.
84. Cheung CM, Wong TY. Treatment of age-related macular degeneration. Lancet. 2013;382:1230-1232.
85. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina. January 18, 2017. [Epub ahead of print].
86. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98:1636-1641.
87. Ng WY, Tan GS, Ong PG, et al. Incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2015;159:557-564.e551.
88. Curtis LH, Hammill BG, Schulman KA, et al. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128:1273-1279.
89. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013;27:787-794.
90. Csaky K, Do DV. Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol. 2009;148:647-656.
91. Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122:146-152.
92. Koh A, Lanzetta P, Lee WK, et al. Recommended guidelines for use of intravitreal aflibercept with a treat-and-extend regimen for the management of neovascular age-related macular degeneration in the Asia-Pacific region: report from a consensus panel. Asia Pac J Ophthalmol (Phila). 2017;6:296-302.
93. Pak KY, Park SW, Byon IS, et al. Treat-and-extend regimen using ranibizumab for polypoidal choroidal vasculopathy: one-year results. Retina. 2017;37:561-567.
94. Cheung GCM, Yeo I, Li X, et al. Argon laser with and without anti-vascular endothelial growth factor therapy for extrafoveal polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;155:295-304.e291.
95. Jeon S, Lee WK, Kim KS. Adjusted retreatment of polypoidal choroidal vasculopathy after combination therapy: results at 3 years. Retina. 2013;33:1193-1200.
96. Cho HJ, Kim HS, Jang YS, et al. Effects of choroidal vascular hyperpermeability on anti-vascular endothelial growth factor treatment for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;156:1192-1200.e1191.
97. Yanagi Y TD, Ng WY, Lee SY, et al. Choroidal vascular hyperpermeability as a predictor of treatment response for polypoidal choroidal vasculopathy. Retina. July 12, 2017. [Epub ahead of print].

age-related macular degeneration; anti-VEGF therapy; polypoidal choroidal vasculopathy

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