Preliminary study on the efficacy of subretinal injection of Aflibercept in the treatment of refractory polypoidal choroidal vasculopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Yu Xiao , Liu Teng , Zou Yuling , Mao Ziqing , Fan Huimin , Chen Zhiping ,  You Zhipeng

1. Department of Ophthalmology, The Affiliated Eye Hospital of Nanchang University, Jiangxi Eye Hospital, Jiangxi Provincial Key Laboratory of Ophthalmology, Jiangxi Provincial Institute of Ophthalmology and Visual Science, Jiangxi Provincial Branch of National Clinical Medical Research Center for Otolaryngological Diseases, Nanchang 330006, China;

Corresponding author：

You Zhipeng, Email: yx19379147887@163.com

Keywords：

Subretinal injection; Refractory polypoidal choroidal vasculopathy; Anti-vascular endothelial growth factor; Aflibercept; Ultra-precision microneedles

DOI：

10.3760/cma.j.cn511434-20231115-00457

Video：

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Objective To observe the efficacy and safety of subretinal injection of Aflibercept for the treatment of refractory or recurrent polypoidal choroidal vasculopathy (PCV). Methods A prospective clinical research. From January to June 2022, 18 patients of 18 eyes with PCV diagnosed in The Affiliated Eye Hospital of Nanchang University were included in the study. All patients underwent best corrected visual acuity (BCVA), indocyanine green angiography and optical coherence tomography (OCT). The BCVA examination was performed using the international standard visual acuity chart, which was converted to logarithm of the minimum angle of resolution (logMAR) visual acuity during statistics. The large choroidal vessel thickness (LVCT), central retinal thickness (CRT), sub-foveal choroidal thickness (SFCT) and retinal pigment epithelium detachment (PED) height were measured by enhanced depth imaging technique of OCT. The choroidal vascular index (CVI) was calculated. There were 18 patients of 18 eyes, 11 males of 11 eyes and 7 females of 7 eyes. The age was (64.22±3.86) years old. The disease duration was (5.22±1.80) years. The patient had received intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs for (7.72±1.36) times. The logMAR BCVA of the affected eyes was 1.28±0.25. The SFCT, CRT, LVCT, PED height were (436.56±9.80), (432.44±44.29), (283.78±27.10), (342.44±50.18) μm, respectively, and CVI was 0.65±0.01. All eyes were treated with a single subretinal injection of 40 mg/ml Aflibercept 0.05 ml (including Aflibercept 2.0 mg). According to the results of OCT and BCVA after treatment, the lesions were divided into active type and static type. The active lesions were treated with intravitreal injection of Aflibercept at the same dose as before. Quiescent lesions were followed up. Examinations were performed 1-3, 6, 9 and 12 months after treatment using the same equipment and methods before treatment. The BCVA, LVCT, CRT, SFCT, PED height, CVI, interretinal or subretinal fluid, lesion regression rate, injection times, and complications during and after treatment were observed. The BCVA, SFCT, CRT, LVCT, PED height and CVI before and after treatment were compared by repeated measures analysis of variance. Results Eighteen eyes received subretinal and/or intravitreal injection of Aflibercept (1.61±0.85) times (1-4 times). At the last follow-up, the polypoid lesions regressed in 4 eyes and PED disappeared in 1 eye. Compared with before treatment, BCVA (F=50.298) gradually increased, CRT (F=25.220), PED height (F=144.16), SFCT (F=69.77), LVCT (F=136.69), CVI (F=72.70) gradually decreased after treatment. The differences were statistically significant (P＜0.001). Macular hole occurred in 1 eye after treatment, and the hole closed spontaneously 3 months after treatment. No serious complications such as retinal tear, retinal detachment, endophthalmitis and vitreous hemorrhage occurred during and after treatment. Conclusion Subretinal injection of Aflibercept is safe and effective in the treatment of refractory PCV.

Citation： Yu Xiao, Liu Teng, Zou Yuling, Mao Ziqing, Fan Huimin, Chen Zhiping, You Zhipeng. Preliminary study on the efficacy of subretinal injection of Aflibercept in the treatment of refractory polypoidal choroidal vasculopathy. Chinese Journal of Ocular Fundus Diseases, 2024, 40(2): 122-128. doi: 10.3760/cma.j.cn511434-20231115-00457 Copy

1.	Goldhardt R, Rosen BS. Polypoidal choroidal vasculopathy[J]. Curr Ophthalmol Rep, 2019, 7(1): 66-72. DOI: 10.1007/s40135-019-00201-4.
2.	Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians[J]. Prog Retin Eye Res, 2016, 53: 107-139. DOI: 10.1016/j.preteyeres.2016.04.002.
3.	Lopez PF, Sippy BD, Lambert HM, et al. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 855-868.
4.	Cox JT, Eliott D, Sobrin L. Inflammatory complications of intravitreal anti-VEGF injections[J]. J Clin Med, 2021, 10(5): 981. DOI: 10.3390/jcm10050981.
5.	Lim TH, Lai TYY, Takahashi K, et al. Comparison of Ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: the EVEREST Ⅱ randomized clinical trial[J]. JAMA Ophthalmol, 2020, 138(9): 935-942. DOI: 10.1001/jamaophthalmol.2020.2443.
6.	Yao TT, Yang Y, Jin XL, et al. Intraocular pharmacokinetics of anti-vascular endothelial growth factor agents by intraoperative subretinal versus intravitreal injection in silicone oil-filled eyes of proliferative diabetic retinopathy: a randomized controlled pilot study[J/OL]. Acta Ophthalmol, 2020, 98(7): e795-e800[2020-02-29]. https://pubmed.ncbi.nlm.nih.gov/32114709/. DOI: 10.1111/aos.14386.
7.	Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: Bevacizumab, Ranibizumab, Aflibercept and ziv-Aflibercept on human retinal pigment epithelium cells in culture[J]. Br J Ophthalmol, 2014, 98(Suppl 1): S11-16. DOI: 10.1136/bjophthalmol-2014-305302.
8.	Kokame GT, deCarlo TE, Kaneko KN, et al. Anti-vascular endothelial growth factor resistance in exudative macular degeneration and polypoidal choroidal vasculopathy[J]. Ophthalmol Retina, 2019, 3(9): 744-752. DOI: 10.1016/j.oret.2019.04.018.
9.	Fine HF, Iranmanesh R, Del Priore LV, et al. Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration[J]. Retina, 2010, 30(10): 1588-1594. DOI: 10.1097/IAE.0b013e3181e2263c.
10.	Sacu S, Stifter E, Vécsei-Marlovits PV, et al. Management of extensive subfoveal haemorrhage secondary to neovascular age-related macular degeneration[J]. Eye (Lond), 2009, 23(6): 1404-1410. DOI: 10.1038/eye.2008.267.
11.	Sharma S, Toth CA, Daniel E, et al. Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(4): 865-875. DOI: 10.1016/j.ophtha.2015.12.002.
12.	Anantharaman G, Sheth J, Bhende M, et al. Polypoidal choroidal vasculopathy: pearls in diagnosis and management[J]. Indian J Ophthalmol, 2018, 66(7): 896-908. DOI: 10.4103/ijo.IJO_1136_17.
13.	Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and Bevacizumab for treatment of neovascular age-related macular degeneration: two-year results[J]. Ophthalmology, 2012, 119(7): 1388-1398. DOI: 10.1016/j.ophtha.2012.03.053.
14.	李凤媚, 宋艳萍. 康柏西普玻璃体内重复注射治疗息肉状脉络膜血管病变疗效及相关因素分析[J]. 眼科新进展, 2019, 39(10): 969-972. DOI: 10.13389/j.cnki.rao.2019.0221.Li FM, Song YP. Efficacy of intravitreal injection of conbercept in polypoidal choroidal vasculopathy and its related factors[J]. Rec Adv Ophthalmol, 2019, 39(10): 969-972. DOI: 10.13389/j.cnki.rao.2019.0221.
15.	Lee WK, Iida T, Ogura Y, et al. Efficacy and safety of intravitreal Aflibercept for polypoidal choroidal vasculopathy in the PLANET Study: a randomized clinical trial[J]. JAMA Ophthalmol, 2018, 136(7): 786-793. DOI: 10.1001/jamaophthalmol.2018.1804.
16.	中华医学会眼科学分会眼底病学组, 中国医师协会眼科医师分会眼底病专业委员会. 中国视网膜下基因治疗药物注射术操作规范推荐专家共识(2022)[J]. 中华实验眼科杂志, 2022, 40(10): 887-893. DOI: 10.3760/cma.j.cn115989-20220808-00366.Fundus Disease Group, Ophthalmology Branch of Chinese Medical Association, and fundus disease Professional Committee of Ophthalmology branch of Chinese Medical Doctor Association. Expert consensus on surgical technique for subretinal injection of gene therapy in China (2022)[J]. Chin J Exp Ophthalmol, 2022, 40(10): 887-893. DOI: 10.3760/cma.j.cn115989-20220808-00366.
17.	Kumagai K, Ogino N, Fukami M, et al. Removal of foveal hard exudates by subretinal balanced salt solution injection using 38-gauge needle in diabetic patients[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(9): 1893-1899. DOI: 10.1007/s00417-020-04756-y.
18.	Avcı R, Mavi Yıldız A, Çınar E, et al. Subretinal coapplication of tissue plasminogen activator and Bevacizumab with concurrent pneumatic displacement for submacular hemorrhages secondary to neovascular age-related macular degeneration[J]. Turk J Ophthalmol, 2021, 51(1): 38-44. DOI: 10.4274/tjo.galenos.2020.72540.
19.	Stout JT, Francis PJ. Surgical approaches to gene and stem cell therapy for retinal disease[J]. Hum Gene Ther, 2011, 22(5): 531-535. DOI: 10.1089/hum.2011.060.
20.	Kolstad KD, Dalkara D, Guerin K, et al. Changes in adeno-associated virus-mediated gene delivery in retinal degeneration[J]. Hum Gene Ther, 2010, 21(5): 571-578. DOI: 10.1089/hum.2009.194.
21.	Peng Y, Tang L, Zhou Y. Subretinal injection: a review on the novel route of therapeutic delivery for vitreoretinal diseases[J]. Ophthalmic Res, 2017, 58(4): 217-226. DOI: 10.1159/000479157.
22.	Treumer F, Wienand S, Purtskhvanidze K, et al. The role of pigment epithelial detachment in AMD with submacular hemorrhage treated with vitrectomy and subretinal co-application of rtPA and anti-VEGF[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(6): 1115-1123. DOI: 10.1007/s00417-017-3620-2.
23.	Sarraf D, Chan C, Rahimy E, et al. Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy[J]. Retina, 2013, 33(8): 1551-1557. DOI: 10.1097/IAE.0b013e31828992f5.
24.	张馨予. 息肉样脉络膜血管病变患者玻璃体腔注射康柏西普治疗的应答及预后影响因素研究[D]. 辽宁: 大连医科大学, 2022.Zhao XY. Study on the response and prognostic factors of intravitreal injection of Conbercept in patients with polypoid choroidal vasculopathy[D]. Liaoning: Dalian Medical University, 2022.
25.	Shen M, Zhou H, Kim K, et al. Choroidal changes in eyes with polypoidal choroidal vasculopathy after anti-VEGF therapy imaged with swept-source OCT angiography[J]. Invest Ophthalmol Vis Sci, 2021, 62(15): 5. DOI: 10.1167/iovs.62.15.5.
26.	Cho JH, Park YJ, Cho SC, et al. Posttreatment polyp regresssion and risk of massive submacular hemorrhage in eyes with polypoidal choroidal vasuculopathy[J]. Retina, 2020, 40(3): 468-476. DOI: 10.1097/IAE.0000000000002384.
27.	Ito A, Maruyama-Inoue M, Kitajima Y, et al. Comparison of one-year results of photodynamic therapy combined with Ranibizumab or Aflibercept for treating polypoidal choroidal vasculopathy[J/OL]. PLoS One, 2020, 15(6): e235213[2020-06-24]. https://pubmed.ncbi.nlm.nih.gov/32579608/. DOI: 10.1371/journal.pone.0235213.
28.	Morizane-Hosokawa M, Morizane Y, Kimura S, et al. Impact of polyp regression on 2-year outcomes of intravitreal Aflibercept injections: a treat-and-extend regimen for polypoidal choroidal vasculopathy[J]. Acta Med Okayama, 2018, 72(4): 379-385. DOI: 10.18926/AMO/56175.
29.	Maruko I, Iida T, Oyamada H, et al. Choroidal thickness changes after intravitreal Ranibizumab and photodynamic therapy in recurrent polypoidal choroidal vasculopathy[J]. Am J Ophthalmol, 2013, 156(3): 548-556. DOI: 10.1016/j.ajo.2013.03.041.
30.	Nagai N, Suzuki M, Minami S, et al. Dynamic changes in choroidal conditions during anti-vascular endothelial growth factor therapy in polypoidal choroidal vasculopathy[J/OL]. Sci Rep, 2019, 9(1): 11389[2019-08-06]. https://pubmed.ncbi.nlm.nih.gov/31388029/. DOI: 10.1038/s41598-019-47738-9.

1. Goldhardt R, Rosen BS. Polypoidal choroidal vasculopathy[J]. Curr Ophthalmol Rep, 2019, 7(1): 66-72. DOI: 10.1007/s40135-019-00201-4.
2. Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians[J]. Prog Retin Eye Res, 2016, 53: 107-139. DOI: 10.1016/j.preteyeres.2016.04.002.
3. Lopez PF, Sippy BD, Lambert HM, et al. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 855-868.
4. Cox JT, Eliott D, Sobrin L. Inflammatory complications of intravitreal anti-VEGF injections[J]. J Clin Med, 2021, 10(5): 981. DOI: 10.3390/jcm10050981.
5. Lim TH, Lai TYY, Takahashi K, et al. Comparison of Ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: the EVEREST Ⅱ randomized clinical trial[J]. JAMA Ophthalmol, 2020, 138(9): 935-942. DOI: 10.1001/jamaophthalmol.2020.2443.
6. Yao TT, Yang Y, Jin XL, et al. Intraocular pharmacokinetics of anti-vascular endothelial growth factor agents by intraoperative subretinal versus intravitreal injection in silicone oil-filled eyes of proliferative diabetic retinopathy: a randomized controlled pilot study[J/OL]. Acta Ophthalmol, 2020, 98(7): e795-e800[2020-02-29]. https://pubmed.ncbi.nlm.nih.gov/32114709/. DOI: 10.1111/aos.14386.
7. Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: Bevacizumab, Ranibizumab, Aflibercept and ziv-Aflibercept on human retinal pigment epithelium cells in culture[J]. Br J Ophthalmol, 2014, 98(Suppl 1): S11-16. DOI: 10.1136/bjophthalmol-2014-305302.
8. Kokame GT, deCarlo TE, Kaneko KN, et al. Anti-vascular endothelial growth factor resistance in exudative macular degeneration and polypoidal choroidal vasculopathy[J]. Ophthalmol Retina, 2019, 3(9): 744-752. DOI: 10.1016/j.oret.2019.04.018.
9. Fine HF, Iranmanesh R, Del Priore LV, et al. Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration[J]. Retina, 2010, 30(10): 1588-1594. DOI: 10.1097/IAE.0b013e3181e2263c.
10. Sacu S, Stifter E, Vécsei-Marlovits PV, et al. Management of extensive subfoveal haemorrhage secondary to neovascular age-related macular degeneration[J]. Eye (Lond), 2009, 23(6): 1404-1410. DOI: 10.1038/eye.2008.267.
11. Sharma S, Toth CA, Daniel E, et al. Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(4): 865-875. DOI: 10.1016/j.ophtha.2015.12.002.
12. Anantharaman G, Sheth J, Bhende M, et al. Polypoidal choroidal vasculopathy: pearls in diagnosis and management[J]. Indian J Ophthalmol, 2018, 66(7): 896-908. DOI: 10.4103/ijo.IJO_1136_17.
13. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and Bevacizumab for treatment of neovascular age-related macular degeneration: two-year results[J]. Ophthalmology, 2012, 119(7): 1388-1398. DOI: 10.1016/j.ophtha.2012.03.053.
14. 李凤媚, 宋艳萍. 康柏西普玻璃体内重复注射治疗息肉状脉络膜血管病变疗效及相关因素分析[J]. 眼科新进展, 2019, 39(10): 969-972. DOI: 10.13389/j.cnki.rao.2019.0221.Li FM, Song YP. Efficacy of intravitreal injection of conbercept in polypoidal choroidal vasculopathy and its related factors[J]. Rec Adv Ophthalmol, 2019, 39(10): 969-972. DOI: 10.13389/j.cnki.rao.2019.0221.
15. Lee WK, Iida T, Ogura Y, et al. Efficacy and safety of intravitreal Aflibercept for polypoidal choroidal vasculopathy in the PLANET Study: a randomized clinical trial[J]. JAMA Ophthalmol, 2018, 136(7): 786-793. DOI: 10.1001/jamaophthalmol.2018.1804.
16. 中华医学会眼科学分会眼底病学组, 中国医师协会眼科医师分会眼底病专业委员会. 中国视网膜下基因治疗药物注射术操作规范推荐专家共识(2022)[J]. 中华实验眼科杂志, 2022, 40(10): 887-893. DOI: 10.3760/cma.j.cn115989-20220808-00366.Fundus Disease Group, Ophthalmology Branch of Chinese Medical Association, and fundus disease Professional Committee of Ophthalmology branch of Chinese Medical Doctor Association. Expert consensus on surgical technique for subretinal injection of gene therapy in China (2022)[J]. Chin J Exp Ophthalmol, 2022, 40(10): 887-893. DOI: 10.3760/cma.j.cn115989-20220808-00366.
17. Kumagai K, Ogino N, Fukami M, et al. Removal of foveal hard exudates by subretinal balanced salt solution injection using 38-gauge needle in diabetic patients[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(9): 1893-1899. DOI: 10.1007/s00417-020-04756-y.
18. Avcı R, Mavi Yıldız A, Çınar E, et al. Subretinal coapplication of tissue plasminogen activator and Bevacizumab with concurrent pneumatic displacement for submacular hemorrhages secondary to neovascular age-related macular degeneration[J]. Turk J Ophthalmol, 2021, 51(1): 38-44. DOI: 10.4274/tjo.galenos.2020.72540.
19. Stout JT, Francis PJ. Surgical approaches to gene and stem cell therapy for retinal disease[J]. Hum Gene Ther, 2011, 22(5): 531-535. DOI: 10.1089/hum.2011.060.
20. Kolstad KD, Dalkara D, Guerin K, et al. Changes in adeno-associated virus-mediated gene delivery in retinal degeneration[J]. Hum Gene Ther, 2010, 21(5): 571-578. DOI: 10.1089/hum.2009.194.
21. Peng Y, Tang L, Zhou Y. Subretinal injection: a review on the novel route of therapeutic delivery for vitreoretinal diseases[J]. Ophthalmic Res, 2017, 58(4): 217-226. DOI: 10.1159/000479157.
22. Treumer F, Wienand S, Purtskhvanidze K, et al. The role of pigment epithelial detachment in AMD with submacular hemorrhage treated with vitrectomy and subretinal co-application of rtPA and anti-VEGF[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(6): 1115-1123. DOI: 10.1007/s00417-017-3620-2.
23. Sarraf D, Chan C, Rahimy E, et al. Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy[J]. Retina, 2013, 33(8): 1551-1557. DOI: 10.1097/IAE.0b013e31828992f5.
24. 张馨予. 息肉样脉络膜血管病变患者玻璃体腔注射康柏西普治疗的应答及预后影响因素研究[D]. 辽宁: 大连医科大学, 2022.Zhao XY. Study on the response and prognostic factors of intravitreal injection of Conbercept in patients with polypoid choroidal vasculopathy[D]. Liaoning: Dalian Medical University, 2022.
25. Shen M, Zhou H, Kim K, et al. Choroidal changes in eyes with polypoidal choroidal vasculopathy after anti-VEGF therapy imaged with swept-source OCT angiography[J]. Invest Ophthalmol Vis Sci, 2021, 62(15): 5. DOI: 10.1167/iovs.62.15.5.
26. Cho JH, Park YJ, Cho SC, et al. Posttreatment polyp regresssion and risk of massive submacular hemorrhage in eyes with polypoidal choroidal vasuculopathy[J]. Retina, 2020, 40(3): 468-476. DOI: 10.1097/IAE.0000000000002384.
27. Ito A, Maruyama-Inoue M, Kitajima Y, et al. Comparison of one-year results of photodynamic therapy combined with Ranibizumab or Aflibercept for treating polypoidal choroidal vasculopathy[J/OL]. PLoS One, 2020, 15(6): e235213[2020-06-24]. https://pubmed.ncbi.nlm.nih.gov/32579608/. DOI: 10.1371/journal.pone.0235213.
28. Morizane-Hosokawa M, Morizane Y, Kimura S, et al. Impact of polyp regression on 2-year outcomes of intravitreal Aflibercept injections: a treat-and-extend regimen for polypoidal choroidal vasculopathy[J]. Acta Med Okayama, 2018, 72(4): 379-385. DOI: 10.18926/AMO/56175.
29. Maruko I, Iida T, Oyamada H, et al. Choroidal thickness changes after intravitreal Ranibizumab and photodynamic therapy in recurrent polypoidal choroidal vasculopathy[J]. Am J Ophthalmol, 2013, 156(3): 548-556. DOI: 10.1016/j.ajo.2013.03.041.
30. Nagai N, Suzuki M, Minami S, et al. Dynamic changes in choroidal conditions during anti-vascular endothelial growth factor therapy in polypoidal choroidal vasculopathy[J/OL]. Sci Rep, 2019, 9(1): 11389[2019-08-06]. https://pubmed.ncbi.nlm.nih.gov/31388029/. DOI: 10.1038/s41598-019-47738-9.

Chinese Journal of Ocular Fundus Diseases

Preliminary study on the efficacy of subretinal injection of Aflibercept in the treatment of refractory polypoidal choroidal vasculopathy

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