Abstract
A panel of 21 international experts are formed by the Asia-Pacific Vitreo-retina Society to work out the consensus and guidelines on polypoidal choroidal vasculopathy (PCV). PCV is a common subtype of neovascular age-related macular degeneration and is more prevalent in Asian populations. Recent advancement in imaging technology allows greater understanding of the disease process of PCV. Furthermore, non–indocyanine green angiography features in optical coherence tomography angiography have been validated for PCV diagnosis and treatment response monitoring. Clinical trials provide new data on the safety and efficacy of various anti–vascular endothelial growth factor (anti-VEGF) agents as well as protocols that aim to improve the sustainability of treatments. In view of the myriads of emerging information, the panel gathered, reviewed, discussed, formulated and voted on the consensus and guidelines of PCV on four areas: 1) disease entity, 2) investigation and diagnosis, 3) treatment options, and 4) management protocol and future development in a five-point Likert scale (strongly agree, agree, neutral, disagree and strongly disagree). We proposed using a consensus score in which the maximum was 100. The summation of the respective “percentages” of experts voting for “agree” or “strongly agree” would be counted as the actual score. Consensus was achieved when the actual score of 75 or more was reached, which meant at least 75 % of the experts had voted for “strongly agree” or “agree” on the consensus statement concerned.
1
Introduction
Neovascular age-related macular degeneration (nAMD) is one of the major vision-threatening diseases globally with increasing prevalence among the aging population. Among Asian nAMD patients, polypoidal choroidal vasculopathy (PCV) has been reported to have a higher prevalence. Indocyanine green angiography (ICGA) and histological studies found morphologic features and clinicopathological characteristics that distinguish PCV from nAMD. Conventionally, ICGA is essential for diagnosing PCV. Nevertheless, ICGA is an invasive procedure and it may not be readily accessible in routine clinical settings. With the advent of noninvasive, high-resolution and high-speed optical coherence tomography (OCT) imaging techniques, a myriad of new clinical data are available to advance our understanding of PCV. In 2021, the Asia-Pacific Ocular Imaging Society (APOIS) PCV Workgroup proposed a combination of validated OCT and color fundus photography features as the diagnostic criteria not requiring ICGA for differentiating PCV from typical nAMD. The ubiquitous utilization of OCT in routine clinical practice has proven OCT to be a practical imaging modality for the identification of PCV features.
It is important to distinguish PCV from typical nAMD for optimizing its management. Clinical trials that comprise both typical nAMD and PCV eyes show varying outcomes in the PCV subgroup. The differing responses of polypoidal lesions which may or may not be completely closed after treatment cause uncertainty in the long-term prognosis of PCV patients. Although clinical trials have demonstrated the efficacy of intravitreal anti–vascular endothelial growth factor (anti-VEGF), there are circumstances that limit compliance to a fixed dosing regimen. The treat and extend (T&E) regimen is a paradigm shift toward an individualized treatment approach for nAMD patients. In 2021, the Asia-Pacific Vitreo-retina Society (APVRS) published a consensus and recommendation for T&E regimen when using anti-VEGF for the management of PCV. Although the term PCV has been established since the mid-1990s, while some aspects of this disease may be well recognized among vitreo-retina specialists, many aspects are still unclear. In addition, there has not yet been a consensus covering the whole aspect of PCV, such as disease entity, investigation and diagnosis, treatment options and management protocol.
In view of the recent advancement of our understanding of PCV with the availability of updated literature and data, the APVRS invited a panel of vitreo-retina experts to participate in issuing consensus statements regarding PCV.
2
Methods
A panel of 21 international vitreo-retina experts from nine countries were invited by the APVRS based on their notable scientific and clinical expertise to take part in this project. The panel reviewed recent publications in the clinicopathology, observational studies and clinical trials of PCV and assembled to discuss and formulate the consensus statements. These statements were categorized as follows: 1) disease entity, 2) investigation and diagnosis, 3) treatment options, and 4) management protocol and future development. A group of four experts was formed for each of these categories to draft the key statements related to that category. The statements were then independently considered by all members of the panel who gave an answer according to a five-point Likert scale, ranging from strongly agree, agree, neutral, disagree and strongly disagree. The definition for achieving a consensus was proposed by one of the authors (DSCL) and endorsed by all the APVRS panel experts. Consensus was achieved when 75 % of responses were in agreement (strongly agree or agree) with the statement. There had not been an international benchmark or definition of when a consensus is reached. Firstly, a simple majority of over 50 % was far from a consensus. Different thresholds (60 %, 70 %, 75 %, 80 % or 90 %) for consensus were tested to investigate the robustness of the result for overall consensus. The threshold of 75 % is commonly used in Delphi studies in the context of core outcome set development to ensure that researchers measure and report those outcomes that are most likely to be relevant to users of their research. After due consideration, the threshold of 75 % was chosen as the consensus criterion in which at least 75 % of the experts had voted for “agree” or “strongly agree” to reach a consensus. Table 1 is a summary of all the key consensus statements and their voting results.
| Section | Questions | Consensus Score * | Strongly Agree | Agree | Neutral | Disagree | Strongly Disagree |
|---|---|---|---|---|---|---|---|
| 1. | Disease entity | ||||||
| 1.1. | Polypoidal choroidal vasculopathy (PCV) is a recurrent exudative and hemorrhagic maculopathy and is characterized by aneurysmal dilatation of the vessels at the terminal of branching neovascular network (BNN). Recently, PCV has been recognized as a variation of neovascular age-related macular degeneration (nAMD) and classified under type 1 macular neovascularization (MNV). | 95 | 11 (52 %) | 9 (43 %) | 1 (5 %) | 0 (0 %) | 0 (0 %) |
| 1.2. | BNN, or the type 1 MNV in PCV, likely arises as a consequence of local ischemia or inflammatory responses, and some of which are linked to pachychoroid phenotype. Polypoidal lesions are formed at the terminal of BNN and may lead to exudative/hemorrhagic changes. | 90 | 8 (38 %) | 11 (52 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 1.3. | PCV is part of the spectrum of pachychoroid disorders, which also include pigment epitheliopathy, pachychoroid neovasculopathy and central serous chorioretinopathy (CSC). | 90 | 5 (24 %) | 14 (66 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 1.4. | Most, but not all, cases of PCV have features of pachychoroid disease such as thickened choroid, dilated choroidal vessels and attenuation of the choriocapillaris. | 90 | 5 (24 %) | 13 (62 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 1.5. | PCV seems to have a predilection for Asian populations and other pigmented races compared to Caucasians. Traditional risk factors of PCV appear to be similar to nAMD and can be broadly classified as demographic or constitutional (such as age, gender), lifestyle or behavioral (such as smoking, diet), medical or physiological (such blood pressure, obesity, increased serum hs-CRP, increased HDL-c), ocular (such as refractive error) and genetics (such as HTRA ). Other factors, such as the previous history of CSC and pachychoroid, are more unique features for PCV. | 90 | 8 (38 %) | 11 (52 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 2. | Investigation and diagnosis | ||||||
| 2.1. | Commonly used diagnostic criteria for PCV include the use of indocyanine green angiography (ICGA) to demonstrate the presence of polypoidal lesions based on EVEREST study or/and the Japanese Study Group criteria. Less invasive imaging modalities, i.e. optical coherence tomography (OCT) as well as OCT angiography (OCTA), are also useful for the diagnosis of PCV. OCT features (subretinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation and sharp-peaked) can be considered as major criteria for diagnosing PCV. | 100 | 13 (62 %) | 8 (38 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 2.2. | PCV can be differentiated from non-PCV nAMD using spectral-domain (SD) OCT/swept-source (SS) OCT in the majority of cases | 91 | 5 (24 %) | 12 (57 %) | 4 (19 %) | 0 (0 %) | 0 (0 %) |
| 2.3. | Where available, multimodal imaging comprising fluorescein angiography, ICGA, SDOCT/SSOCT and OCTA provides the most comprehensive assessment at baseline visit. | 100 | 17 (81 %) | 4 (19 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 2.4. | SDOCT/SSOCT should be performed at baseline and repeated for disease activity assessment. | 100 | 18 (86 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 3. | Treatment options | ||||||
| 3.1. | The first-line treatment for PCV can be either anti–vascular endothelial growth factor (anti-VEGF) monotherapy or combined anti-VEGF and photodynamic therapy (PDT). | 95 | 15 (71 %) | 3 (14 %) | 1 (5 %) | 0 (0 %) | 0 (0 %) |
| 3.2. | Level 1 evidence supports the use of anti-VEGF monotherapy or combination therapy (anti-VEGF plus verteporfin PDT) as key therapeutic approaches to the treatment of active PCV. | 90 | 10 (47 %) | 9 (43 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 3.3. | Monotherapy with anti-VEGF treatment is effective in many cases of PCV and can be used initially as monotherapy. | 95 | 14 (66 %) | 6 (29 %) | 1 (5 %) | 0 (0 %) | 0 (0 %) |
| 3.4. | In order to achieve optimal visual improvement and long-term maintenance of vision, closure of active polypoidal lesions is an important goal when treating PCV. | 90 | 7 (33 %) | 12 (57 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 3.5. | For patients with PCV who may not be able to have regular long-term follow-up, combination therapy should be considered as a preferred first-line treatment. | 86 | 5 (24 %) | 13 (62 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 3.6. | For patients with a subfoveal, small PCV lesion (e.g. one disc area or smaller) with good vision (e.g. 20/30 or better) and recent disease activity, anti-VEGF monotherapy can be considered a first-line treatment. | 100 | 16 (76 %) | 5 (24 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 3.7. | Surgical management of large submacular hemorrhage from PCV may require pneumatic gas displacement or vitrectomy surgery with submacular drainage of blood. | 86 | 6 (29 %) | 12 (57 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 3.8. | Thermal laser ablation of active polypoidal lesions in combination with anti-VEGF therapy may be considered in an extrafoveal location. | 86 | 6 (29 %) | 12 (57 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 3.9. | If PDT is unavailable, focal laser photocoagulation to polypoidal lesions located in an extrafoveal location may be considered. | 86 | 5 (24 %) | 13 (62 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 4 | Management protocol and future development | ||||||
| 4.1. | Active PCV is defined as one or more of the following: new onset of symptoms suggestive of neovascularization, fluid (subretinal, intraretinal or sub-RPE), hemorrhage, hard exudates at the macula, in the presence of polypoidal lesions on SDOCT and/or ICGA. | 90 | 16 (76 %) | 3 (14 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 4.2. | The presence of pachychoroid and choroidal hyperpermeability on ICGA indicate a higher likelihood of suboptimal or nonresponse to anti-VEGF therapy and benefit from combination therapy (anti-VEGF plus verteporfin PDT). | 43 | 1 (5 %) | 8 (38 %) | 11 (52 %) | 0 (0 %) | 0 (0 %) |
| 4.3. | The absence of pachychoroid and choroidal hyperpermeability on ICGA indicate poorer outcomes when combination therapy is applied, compared to anti-VEGF alone. | 38 | 1 (5 %) | 7 (33 %) | 11 (52 %) | 0 (0 %) | 0 (0 %) |
| 4.4. | For cases with inadequate or suboptimal response during treatment, either switching to other anti-VEGF agents or adding rescue PDT can be considered. | 100 | 13 (62 %) | 8 (38 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 4.5. | Switching to another anti-VEGF or newer agents after three initial treatments may be required to improve response to treatment. | 76 | 2\ (10 %) | 14 (66 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 4.6. | The efficacy and safety of new therapeutic agents such as faricimab should be studied in a randomized clinical trial. | 86 | 8 (38 %) | 10 (48 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 4.7. | When anti-VEGF monotherapy is selected, a treat-and-extend (T&E) treatment regimen is preferred. | 95 | 7 (33 %) | 13 (62 %) | 1 (5 %) | 0 (0 %) | 0 (0 %) |
| 4.8. | Three to six initial monthly injections may be required for disease inactivity and polyp inactivation before the T&E phase to control disease in the long term. | 90 | 7 (33 %) | 12 (57 %) | 2 (10 %) | 0 (0 %) | 0 (0 %) |
| 4.9. | T&E regimen using anti-VEGF agents optimally controls disease activity, minimizes recurrences and improves visual outcomes after the induction phase. | 95 | 5 (24 %) | 15 (71 %) | 1 (5 %) | 0 (0 %) | 0 (0 %) |
| 4.10. | The efficacy and safety of the port delivery system of ranibizumab should be assessed. | 67 | 4 (19 %) | 10 (48 %) | 6 (28 %) | 1 (5 %) | 0 (0 %) |
| 4.11. | There is a need to study the role of OCTA in the diagnosis and management of PCV e.g. recurrence from branching vascular network, identification of polypoidal lesions. | 76 | 6 (29 %) | 12 (57 %) | 3 (14 %) | 0 (0 %) | 0 (0 %) |
| 4.12. | One of the future perspectives is to establish prognostic factors guiding selection of the best therapeutic option for any given case. | 100 | 9 (43 %) | 12 (57 %) | 0 (0 %) | 0 (0 %) | 0 (0 %) |
| 4.13. | One of the future perspectives is to develop a polygenic risk score for PCV. | 76 | 1 (5 %) | 15 (71 %) | 5 (24 %) | 0 (0 %) | 0 (0 %) |
| 4.14. | Gene therapy for continuous production of anti-VEGF protein could reduce the treatment burden and establish long-term disease stability. | 71 | 0 (0 %) | 15 (71 %) | 6 (29 %) | 0 (0 %) | 0 (0 %) |
* Consensus Score (CS) was defined as the value of the summation of the “strongly agree, and “ “agree” percentages; CS ≥ 75 was considered “consensus achieved” and CS < 75 was “consensus not reached”. Only 4 statements were “consensus not achieved” (with bold and underline)
3
Results
Consensus statements
3.1
Disease entity
PCV is a recurrent exudative and hemorrhagic maculopathy and is characterized by aneurysmal dilatation of the vessels at the terminal of branching neovascular network. Recently, PCV has been recognized as a variation of nAMD and classified under type 1 macular neovascularization (MNV). (Consensus score: 95 [strongly agree: 52 %; agree: 43 %])
The presence of polypoidal lesion ( Figs. 1 and 2 ) is one of the hallmark characteristics of PCV . Dynamic ICGA has revealed visible pulsation of the polypoidal lesion associated with subretinal haemorrhage. Spectral-domain (SD) OCT studies observe hyporeflective round subretinal pigment epithelium (RPE) ring-like structures with hyperreflective outline that correlate with polypoidal lesions. OCT and histological studies have found the abnormal vascular network in PCV above the Bruch membrane that colocalize with type 1 MNV.
Pulsatile polypoidal lesion in dynamic ICGA suggest its arterial origin, however, pulsations have not been revealed in all cases. Furthermore, the sub-RPE ring-like structure has not been observed in a proportion of PCV cases in SDOCT studies, and internal structures may exist within some polypoidal lesions. Therefore, controversy still surrounds whether the vascular dilations in PCV are aneurysms. The APOIS PCV Workgroup recommended the term “polypoidal lesions” until better understanding of the internal structures of the lesions is available.
Branching neovascular network (BNN), or the type 1 MNV in PCV, likely arises as a consequence of local ischemia or inflammatory responses, and most of which are linked to pachychoroid phenotype. Polypoidal lesions are formed at the terminal of BNN and may lead to exudative/hemorrhagic changes. (Consensus score: 90 [strongly agree: 38 %; agree: 52 %])
PCV is part of the spectrum of pachychoroid disorders, which also include pigment epitheliopathy, pachychoroid neovasculopathy and central serous chorioretinopathy. (Consensus score: 90 [strongly agree: 24 %; agree: 66 %])
Most, but not all, cases of PCV have features of pachychoroid disease such as thickened choroid, dilated choroidal vessels and attenuation of the choriocapillaris. (Consensus score: 86 [strongly agree: 24 %; agree: 62 %])
Enhance depth imaging in SDOCT and swept-source (SS) OCT studies have identified increased subfoveal choroidal thickness in PCV eyes. Abnormally dilated outer choroidal vessels (pachy vessels) with a tapered end were also visualized in en face SDOCT and SSOCT studies. Furthermore, the lack of tessellation on color fundus photography and the presence of choroidal vascular hyperpermeability (CVH) on ICGA are additional signs that characterize the pachychoroid morphology, which is found to be present in a significant proportion of PCV eyes. It is postulated that the increased caliber of outer choroidal vasculature could lead to venous overload choroidopathy. Subsequent to the venous stasis within the abnormally dilated outer choroidal vessels, thinning of the inner choroidal layer occurs. A number of studies that utilized OCT angiography (OCTA) have found increased areas of flow signal void in en face scans of the choriocapillaris layer in eyes affected by pachychoroid diseases. In later stages, MNV may arise as a consequence of local ischemia or inflammatory responses.
Nevertheless, not all PCV eyes consist of thickened choroid, dilated choroidal vessels and CVH. Lee et al. reported that a cohort of PCV eyes had wide variability in subfoveal choroidal thickness. Therefore, the absence of pachychoroid features may not necessarily discern PCV from typical nAMD. Rather, it is considered part of the spectrum of pachychoroid disorders, which also include pigment epitheliopathy, pachychoroid neovasculopathy and central serous chorioretinopathy (CSC).
PCV seems to have a predilection for Asian populations and other pigmented races compared to Caucasians. Traditional risk factors of PCV appear to be similar to nAMD; they can be broadly classified as demographic or constitutional (such as age, gender), lifestyle or behavioral (such as smoking, diet), medical or physiological (such blood pressure, obesity, increased serum hs-CRP, increased HDL-c), ocular (such as refractive error) and genetics (such as HTRA ). Other factors, such as the previous history of CSC and pachychoroid, are more unique features for PCV. (Consensus score: 90 [strongly agree: 38 %; agree: 52 %])
In the Asia-Pacific region, PCV has been reported in up to 50 % of nAMD patients which is more frequent than those observed among predominantly White populations where prevalence of PCV is reported to be about 10–20 % of nAMD cases. However, studies that routinely utilized ICGA in nAMD patients of predominantly European ancestry detected higher rates of PCV ranged from 25 % to 31 %.
A large-scale, population-based study of Japanese subjects reported that systemic factors, including male gender and smoking, were strongly associated with PCV. A meta-analysis found an increased level of C-reactive protein was also significantly associated with PCV. Candidate gene analysis identified a number of AMD-associated gene loci (ARMS2, HTRA1, CFH, C2, CFB, RDBP, SKIV2L, CETP, 8p21, and 4q12) that were strongly associated with PCV. The differences in the frequencies of risk alleles between Asian and White AMD patients may play a role in the variations of clinical manifestations between ethnic groups.
3.2
Investigation and diagnosis
Commonly used diagnostic criteria for PCV include the use of ICGA to demonstrate the presence of polypoidal lesions based on the EVEREST study or/and the Japanese Study Group criteria. Less invasive imaging modalities, i.e. OCT as well as OCTA, are also useful for the diagnosis of PCV. OCT features (sub-RPE ring-like lesion, en face OCT complex RPE elevation and sharp-peaked) can be considered as major criteria for diagnosing PCV. (Consensus score: 100 [strongly agree: 62 %; agree: 38 %])
Conventionally, ICGA is essential for diagnosing PCV, with a set of specific angiographic signs recommended by clinical experts or by reading centers in clinical trials. Nevertheless, performing ICGA is invasive and time-consuming, and it may not be accessible for routine diagnosis in some clinical settings. With the availability of new imaging data from SDOCT/SSOCT scans, ophthalmologists have advanced in understanding the clinical manifestations of PCV. A number of studies have validated the use of non-ICGA imaging features for discerning PCV from typical nAMD cases that yielded high sensitivity and specificity of over 80–90 %.
PCV can be differentiated from non-PCV nAMD using SDOCT/SSOCT in the majority of cases. (Consensus score: 81 [strongly agree: 24 %; agree: 57 %])
Clinic-based studies that use SDOCT/SSOCT found high diagnostic yield for PCV. In one study, the presence of three out of four SDOCT features (sharp pigment epithelial detachment [PED], multiple PEDs, PED notch and round sub-RPE ring-like structure) had sensitivity and specificity of over 90 % in distinguishing PCV ( Figs. 1 and 2 ). Chikitmongkol et al. studied the combination of fundus photography appearance (notched or hemorrhagic PED) and OCT signs (sharp PED, notched PED and hyperreflective right under PED) and reported that the presence of two out of four features also had a diagnostic accuracy of over 90 % for PCV. A validation study was performed using the combination of three major SDOCT imaging characteristics recommended by the APOIS PCV Workgroup (sub-RPE ring-like lesion, en face OCT complex RPE elevation and sharp-peaked PED) among a cohort of 80 MNV patients from Singapore and Italy yielded diagnostic accuracy of 82 %.
Where available, multimodal imaging comprising fluorescein angiography, ICGA, SDOCT/SSOCT and OCTA provides the most comprehensive assessment at baseline visit. (Consensus score: 100 [strongly agree: 81 %; agree: 19 %])
SDOCT/SSOCT should be performed at baseline and repeated for disease activity assessment. (Consensus score: 100 [strongly agree: 86 %; agree: 14 %])
The non-fulfilment of the non-ICGA imaging diagnostic criteria cannot be used to exclude PCV. Clinicians are encouraged to look for such SDOCT/SSOCT features to become vigilant in suspecting PCV. To date, ICGA remains as the gold standard for PCV diagnosis. ICGA provides an en face view of the posterior segment of the eye to allow the detection of the entire PCV lesion as well as extrafoveal lesions. Nevertheless, the interpretation of ICGA can sometimes be unreliable. A study reported that reading centers had a certain proportion of screen failures from patients recruited by retinal specialists with considerable expertise for PCV clinical trials. Simultaneous examination of multimodal imaging including SDOCT/SSOCT scans helps to differentiate PCV from other mimicking conditions that appear with hot spots (pseudo-polyps) on ICGA, such as type 3 neovascularization and retinal arterial macroaneurysm.
Further to the evaluation of treatment-naïve PCV eyes, the APOIS PCV Workgroup also assessed the SDOCT features for differentiating PCV from typical nAMD in eyes with persistent fluid after initial anti-VEGF therapy. The presence of sub-RPE ring-like lesion, sharp-peaked PED and orange nodule was able to differentiate eyes with active PCV from typical nAMD with an area under the receiver operating characteristic curve of 0.85 ( Figs. 1 and 2 ).
3.3
Treatment options
3.3.1
Medical treatment
The first-line treatment for PCV can be either anti-VEGF monotherapy or combined anti-VEGF and photodynamic therapy (PDT). (Consensus score: 85 [strongly agree: 71 %; agree: 14 %])
Level 1 evidence supports the use of anti-VEGF monotherapy or combination therapy (anti-VEGF plus verteporfin PDT) as key therapeutic approaches to the treatment of active PCV. (Consensus score: 90 [strongly agree: 47 %; agree: 43 %])
Monotherapy with anti-VEGF treatment is effective in many cases of PCV and can be used initially as monotherapy. (Consensus score: 95 [strongly agree: 66 %; agree: 29 %])
In order to achieve optimal visual improvement and long-term maintenance of vision, closure of active polypoidal lesions is an important goal when treating PCV. (Consensus score: 90 [strongly agree: 33 %; agree: 57 %])
For patients with PCV who may not be able to have regular long-term follow-up, combination therapy should be considered as a preferred first-line treatment. (Consensus score: 86 [strongly agree: 24 %; agree: 62 %])
The EVEREST II study showed the efficacy of combined PDT with intravitreal ranibizumab treatment for PCV and reported superior visual gain compared to intravitreal ranibizumab monotherapy at 24 months (9.6 vs. 5.5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters gain). On the other hand, the PLANET study showed that the efficacy of intravitreal aflibercept monotherapy had noninferior visual outcomes compared to intravitreal aflibercept combined with rescue PDT treatment (10.7 versus 10.8 ETDRS letters gain). Therefore, both anti-VEGF monotherapy or combined anti-VEGF and PDT have level 1 evidence to support their efficacies for the first-line treatment of active PCV.
In the EVEREST II study, combined PDT with intravitreal ranibizumab achieved a higher complete closure rate for active polypoidal lesions compared with intravitreal ranibizumab monotherapy (56.6 % vs. 26.7 %) at 24 months. The LAPTOP study compared PDT monotherapy with intravitreal ranibizumab monotherapy and reported a superior visual outcome achieved by the intravitreal ranibizumab arm. Although polypoidal lesion closure rate was not reported in the LAPTOP study, the outcomes imply that anti-VEGF monotherapy could achieve a good functional outcome regardless of complete polypoidal lesion closure. In the PLANET study, despite less than 40 % of eyes achieved a complete closure of polypoidal lesion, nearly 80 % of eyes had fluid-free retina based on OCT at the end of the clinical trial. It appears that the inactivation of polypoidal lesion ( Fig. 2 ) may allow good functional outcome with or without its complete closure. Nonetheless, long-term prospective results will validate whether the complete closure of polypoidal lesions as a treatment endpoint is required to achieve optimal outcomes.
For patients with a subfoveal, small PCV lesion (e.g. one disc area or smaller) with good vision (e.g. 20/30 or better) and recent disease activity, anti-VEGF monotherapy can be considered a first-line treatment. (Consensus score: 100 [strongly agree: 76 %; agree: 24 %])
The subgroup analysis of PCV patients in the PLANET study reported the efficacy of intravitreal anti-VEGF monotherapy was noninferior to those who received rescue PDT treatment. Furthermore, PDT carries the potential risks for vision-threatening complications including choroidal ischemia, RPE rips and subretinal hemorrhage. Patients who receive multiple repeated PDT may be at risk of RPE atrophy in the long term.
3.3.2
Surgical treatment
Surgical management of large submacular hemorrhage from PCV may require pneumatic gas displacement or vitrectomy surgery with submacular drainage of blood. (Consensus score: 86 [strongly agree: 29 %; agree: 57 %])
The natural course of large submacular hemorrhage secondary to PCV is generally poor. One study showed that over 90 % of eyes presented with submacular hemorrhage had visual outcome of 20/200 or worse. Submacular hemorrhage induces irreversible retinal damage due to a combination of factors, including the formation of a diffusion barrier by the clot, mechanical trauma to the outer segments due to clot contraction, and iron toxicity. Pneumatic displacement of submacular hemorrhage through gas injection, with or without tissue plasminogen activator (tPA), had been shown to achieve complete displacement of blood in 50–100 % of cases, in which 45–80 % had visual acuity improvement to better than 20/200. The exact role of tPA is yet to be fully determined and further studies are warranted. Vitrectomy is a surgical approach for the displacement or removal of submacular hemorrhage. The safety and efficacy of submacular hemorrhage displacement by intravitreal gas injection versus vitrectomy approach is yet to be determined in prospective clinical trials. Some may attempt intravitreal gas displacement followed by vitrectomy if the initial blood displacement is insufficient.
Thermal laser ablation of active polypoidal lesions in combination with anti-VEGF therapy may be considered in an extrafoveal location. (Consensus score: 86 [strongly agree: 29 %; agree: 57 %])
If PDT is unavailable, focal laser photocoagulation to polypoidal lesions located in an extrafoveal location may be considered. (Consensus score: 86 [strongly agree: 24 %; agree: 62 %])
Since PDT may not be readily accessible in some clinic settings, photocoagulation to extrafoveal polypoidal lesions from PCV can be considered in cases where it is visible on ICGA. If there is a significant serosanguinous elevation that accompanies the extrafoveal PCV lesions, anti-VEGF therapy can be initiated followed by thermal laser ablation once the fluid regresses.
3.4
Management protocol and future perspective
3.4.1
Management protocol
Active PCV is defined as one or more of the following: new onset of symptoms suggestive of neovascularization, fluid (subretinal, intraretinal or sub-RPE), hemorrhage, hard exudates at the macula, in the presence of polypoidal lesions on SDOCT and/or ICGA. (Consensus score: 90 [strongly agree: 76 %; agree: 14 %])
The presence of pachychoroid and choroidal hyperpermeability on ICGA indicate a higher likelihood of suboptimal or nonresponse to anti-VEGF therapy and benefit from combination therapy (anti-VEGF plus PDT). (Consensus not achieved with a score of 43 [strongly agree: 5 %; agree: 38 %])
The absence of pachychoroid and choroidal hyperpermeability on ICGA indicate poorer outcomes when combination therapy is applied, compared to anti-VEGF alone. (Consensus was not achieved with a score of 38 [strongly agree: 5 %; agree: 33 %])
Similar to nAMD, clinical and SDOCT features are important for the prompt recognition of active PCV which includes any one of the following features: 1) significant vision loss ( > 5 ETDRS letters), 2) sub-RPE or subretinal hemorrhage, and 3) intraretinal/subretinal and/or sub-RPE fluid.
CVH is characterized by multifocal areas of hyperfluorescence with ill-defined margins during the late phase and corresponding filling defects during the early phase of ICGA. Abnormally dilated choroidal veins are usually observed alongside CVH on ICGA. CVH is one of the salient features of pachychoroid. Nevertheless, CVH does not always exist in pachychoroid and it has been reported only in 11–68 % of eyes with thick choroid. CVH represents functional disturbance in pachychoroid and therefore, it is possible to have the anatomical abnormality of dilated choroidal veins without hyperpermeability. Combination treatment with PDT has been reported to be more effective than intravitreal anti-VEGF monotherapy in terms of vision gain compared to nonpachychoroid PCV in these cases of CVH. Eyes with CVH responded well to combination treatment because PDT occludes abnormal hyperpermeable choroidal vessels and reduces the increased hydrostatic pressure of the choroid. A number of studies reported that eyes with CVH were more likely to respond suboptimally to intravitreal ranibizumab treatment alone than those without. On the other hand, a number of studies reported that PCV eyes that had a significant reduction in choroidal thickness after anti-VEGF therapy could respond well. Further prospective clinical trials that study the modulation of the functional or anatomical aspects of pachychoroid may establish its roles as a biomarker for treatment in PCV patients.
For cases with inadequate or suboptimal response during treatment, either switching to other anti-VEGF agents or adding rescue PDT can be considered. (Consensus score: 100 [strongly agree: 62 %; agree: 38 %])
Switching to another anti-VEGF or newer agents after 3 initial treatments may be required to improve response to treatment. (Consensus score: 76 [strongly agree: 10 %; agree: 66 %])
The efficacy and safety of new therapeutic agents such as faricimab should be studied in a randomized clinical trial. (Consensus score: 86 [strongly agree: 38 %; agree: 48 %])
A number of studies evaluated PCV eyes that had persistent subretinal or intraretinal fluid after the initial loading phase of three-monthly intravitreal anti-VEGF monotherapy and observed an increase in the vison as well as disease activity remission rates after switching to another intravitreal anti-VEGF agent with or without PDT. Newer anti-VEGF agents were developed to improve the treatment durability as well as to minimize the treatment burden of nAMD patients. These agents had been evaluated for the safety and efficacy in PCV patients. In the phase 3 HAWK and HARRIER clinical trials, brolucizumab, a humanized monoclonal single-chain variable fragment (scFv) that binds and inhibits VEGF-A, was found to have similar efficacy but more durable than the fixed dosing regimen of intravitreal aflibercept. Subgroup analysis of Japanese PCV patients from the HAWK trial showed excellent anatomical and functional outcomes with 8- or 12-weekly injections compared to 8-weekly injections with aflibercept. In a case series that received three monthly intravitreal injections of brolucizumab, the polypoidal lesion regression rate was 78.9 % with significantly improved functional outcomes. However, due to the significant rate of intraocular inflammation, careful selection is warranted and posttreatment close monitoring is necessary for the prompt management of intraocular inflammation as well as to prevent irreversible vision loss from occlusive vasculitis.
Faricimab is a bi-specific monoclonal antibody that binds to both VEGF-A and angiopoietin-2 (Ang-2). In nAMD, upregulation of Ang-2 promotes vascular leakage in combination with VEGF-A. The TENAYA and LUCERNE clinical trials demonstrated noninferiority of intravitreal faricimab that extended to 16-week treatment intervals after the initial loading phase compared to fixed eight weekly intravitreal injection of aflibercept. In 2024, a systematic review identified seven clinical studies with data from over 150 PCV eyes that received intravitreal faricimab treatment. The meta-analysis of these studies showed significant vision gain, reduction of central retinal thickness, as well as polypoidal lesion closure rate of 48.7 %. Five of the studies were treatment-naïve PCV eyes and two studies were switch-over cases, in which 57–67 % experienced fluid reduction and 21 % were able to extend their treatment interval. It seems that some PCV nonresponders may benefit from switching to intravitreal faricimab. However, long-term efficacy studies and controlled head-to-head clinical trials are warranted.
When anti-VEGF monotherapy is selected, a T&E treatment regimen is preferred. (Consensus score: 95 [strongly agree: 33 %; agree: 62 %])
Three to six initial monthly injections may be required for disease inactivity and polyp inactivation before the T&E phase to control disease in the long term. (Consensus score: 90 [strongly agree: 33 %; agree: 57 %])
T&E regimen using anti-VEGF agents optimally controls disease activity, minimizes recurrences and improves visual outcomes after the induction phase. (Consensus score: 95 [strongly agree: 24 %; agree: 71 %])
The T&E regimen is becoming the preferred management option for nAMD patients because it has been shown to reduce the total number of clinic visits by extending the treatment intervals while achieving comparable or favorable visual outcomes compared with to treatment regimens such as the fixed dosing or pro re nata regimens.
In the PLANET study, a number of PCV patients received T&E regimen during the second year in which 41.2 % of patients were able to extend the treatment interval up to 12 weeks and maintaining vision gain at the end of the 24-month study. A subgroup of PCV patients in the ALTAIR study showed over 60 % of them were able to extend up to 12-week treatment intervals before week 96 with vision maintained at week 96. Another randomized controlled trial of 53 PCV patients reported noninferiority of a T&E regimen compared to fixed dosing of intravitreal aflibercept with complete polypoidal lesion regression rates of 41.6 % versus 55.2 % without significant statistical difference. Several real-world studies also showed the efficacy of the T&E regimen that achieved approximately 50 % polypoidal regression rates.
In view of studies that demonstrated efficacious outcomes of the T&E regimen of intravitreal anti-VEGF therapy in PCV eyes and its practicality in reducing the number of clinic visits, a panel of experts from the APVRS published the consensus and recommendations for the T&E regimens for the management of nAMD and PCV patients. After the loading treatment of three consecutive monthly doses of intravitreal anti-VEGF, the treatment intervals can be extended by two to four weeks up to 12–16 weeks from the prior treatment visit. Once disease activity is detected, it is recommended to shorten the treatment interval by two to four weeks until the disease is inactive, after which the treatment interval can be extended again by two to four weeks. The panel recommends intraretinal fluid should be dried completely while a persistent small amount of subretinal fluid can be tolerated as long as its amount is stable.
3.4.2
Future development
The efficacy and safety of the port delivery system of ranibizumab should be assessed. (Consensus score: 67 [strongly agree: 19 %; agree: 48 %])
The port delivery system (PDS) is a scleral implant that contains a small reservoir filled with ranibizumab for controlled and sustained drug release which can be refilled through a self-sealing septum. The phase 3 ARCHWAY clinical trial had shown the efficacy of PDS implant with ranibizumab refilled every 24 weeks being noninferior to monthly ranibizumab treatments over nine months and two years. However, the PDS treatment arm had higher rates of adverse events including vitreous hemorrhage and endophthalmitis. There are a number of ongoing clinical trials designed to evaluate the safety and efficacy of PDS in different ethnic groups of nAMD patients, compared to the T&E treatment regimen and with other anti-VEGF agents. The progress of some of these clinical trials has been delayed due to PDS septum dislodgement problems during the refill procedure that prompted the recall of PDS implant and drug refill tools in 2022. To gain a comprehensive understanding of the PDS, further large studies are needed, exploring long-term efficacy, safety, satisfaction, preference and cost in real-world settings.
There is a need to study the role of OCTA in the diagnosis and management of PCV, for example, recurrence from branching vascular network, identification of polypoidal lesions. (Consensus score: 86 [strongly agree: 29 %; agree: 57 %])
OCTA has the advantage of being a noninvasive investigation tool for depth-resolved examination of retinal and choroidal vasculature without dye interference. OCTA can detect the presence of type 1 MNV or BNN. In a cohort of 277 patients with pachychoroid and CSC, Ng et al. reported the high sensitivity of OCTA for the detection of type 1 MNV was 78–81 % and the specificity was 96–97 % when compared to the reference standard that utilized multimodal imaging including ICGA. Nevertheless, the interpretation of OCTA in PCV eyes can be influenced by the presence of large hemorrhagic PED and subretinal fibrosis. Segmentation error, projection artifact and the limitation in scan area to detect extrafoveal lesions may lower the reliability of commercially available OCTA as a diagnostic tool. The reported rate of polypoidal lesion detection using OCTA in the literature ranges from 50 % to 90 %. The inconsistency of polypoidal lesion detection on OCTA can be due to turbulent flow within the lumen of polypoidal lesions which causes variable appearances of the signal flow maps.
OCTA studies of the inner choroid revealed increased flow signal voids in the choriocapillaris layer, which furthered our understanding of the evolution of pachychoroid disorders and venous overload choroidopathy that may subsequently lead to pachychoroid neovasculopathy. OCTA studies will allow further understanding of PCV disease mechanism, and the future enhancement in OCTA image acquisition and processing will allow studies to validate its reliability in clinical practice for the detection of PCV and its activity status.
One of the future perspectives is to establish prognostic factors guiding selection of the best therapeutic option for any given case. (Consensus score: 100 [strongly agree: 43 %; agree: 57 %])
One of the future perspectives is to develop a polygenic risk score for PCV. (Consensus score: 76 [strongly agree: 5 %; agree: 71 %])
Gene therapy for continuous production of anti-VEGF protein could reduce the treatment burden and establish long-term disease stability. (Consensus score: 71 [strongly agree: 0 %; agree: 71 %])
With the recent advancement in imaging technology, further understanding of the changes in choroidal vasculature and microstructure is important toward establishing the phenotypic classification of the choroid as well as to develop choroid-guided treatment strategies for PCV. Quantification studies of the morphometrics of the choroid have documented the changes in response to PCV treatment as well as prediction for disease recurrence. A number of studies have reported the changes in subfoveal choroidal thickness in PCV eyes after intravitreal anti-VEGF therapies. Choroidal vascular density on ultra-widefield ICGA is being evaluated as a predictor for PCV response to treatments. Choroidal vascularity index measures the intraluminal changes relative to the interstitial spaces within the choroid, which is useful toward the comprehension of PCV responses to various treatments. Artificial intelligence is being applied to the imaging analysis of volumetric studies of the choroid. These important recent research findings contribute toward establishing the future biomarkers for PCV therapies and prognostication.
Studies have shown the association between genetic variants and various clinical manifestations in nAMD and PCV. Genetic factors may well play a significant role toward the differences in responses to treatments which associate with the variations in ethnicity and phenotypes among individuals. A combination of high-risk gene variants including ARMS2 , CFH and others were observed to be significantly associated with the need for additional intravitreal anti-VEGF injections, higher number of injections and vision outcome at 12 months of a clinical trial with intravitreal aflibercept monotherapy for PCV. Future collaborative studies are necessary to advance our understanding of the influence of ethnicity, genetics, epigenetics and pharmacogenetics on PCV management.
Gene therapy allows the possibility of expressing more than one active agent over time, with the capability of multiple therapeutic targets in the angiogenesis cascade in addition to VEGF. Hence, gene therapy potentially results in greater efficacy and sustainability over current intravitreal anti-VEGF therapies. Further research is necessary to enhance the route of therapeutic administration as well as to mitigate any adverse immune-mediated responses toward the gene therapy vector.
All of the 21 invited experts participated in the grading of every key statement. The key statements and the poll results are shown in Table 1 . A flow chart that summarizes the salient points from the experts’ consensus on PCV management strategy is illustrated in Fig. 3 .
