EYES OF THE WORLD

Clinical Implications of Unique RAP and PCV Prevalence Patterns in Asian Patients

DISPATCHES FROM INTERNATIONAL COLLEAGUES ON GLOBAL ISSUES IN RETINA

ICHIRO MARUKO, MD ∙ TOMOHIRO IIDA, MD

Neovascular exudative age-related macular degeneration is a leading cause of blindness in patients over 50 years of age in developed countries. It is classified into three types: polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) and typical AMD represented by classic and/or occult choroidal neovascularization as documented by indocyanine green angiography^1,2

Nowadays, anti-vascular endothelial growth factor therapy (eg, ranibizumab or bevacizumab) is the most common intervention used to maintain and improve visual acuity in AMD.^3,4 However, more than a few AMD patients are nonresponders to anti-VEGF therapy Cho and associates⁵ reported that these cases possibly included PCV, and could be improved by the combination of anti-VEGF therapy and verteporfin photodynamic therapy (PDT). This may indicate there are quite a few “hidden” PCV patients who have not undergone ICG angiography.

The number of patients in Japan with neovascular AMD was thought to be fewer than that in western countries.^6-11 However, Miyazaki and associates¹² reported that the five-year incidence for AMD in the Hisayama study of the Japanese population was 0.8%; this result was the similar to 0.9% found in the Beaver Dam Eye study and 1.1% in the Blue Mountains Eye study.^13,14 These data may indicate the prevalence of AMD in Japan is increasing and catching up with that in western countries.

In a recent study, Maruko and associates¹⁵ reported that among 289 patients, 158 (54.7%) were diagnosed with PCV, 102 (35.3%) with typical AMD and 13 (4.5%) with RAP. All patients successfully underwent ICG angiography.

Indocyanine green angiogram demonstrates typical polypoidal lesions with branching vascular network at the macular area. IMAGE COURTESY OF TOMOHIRO IIDA, MD

The proportion of PCV in neovascular AMD was more than 50% in Japanese patients. Yannuzzi and associates¹⁶ reported that the proportion of PCV was approximately 5% to 10% in the United States. Sho and associates¹⁷ stated that the proportion of PCV was 24% of AMD in Japanese patients, Wen and associates¹⁸ reported 22.3% in Chinese patients, and Byeon and associates¹⁹ reported 24.6% in Korean patients. These are thought to be due to ethnic differences. At the same time, the proportion of RAP in neovascular AMD was 10% to 15% in the United States; this number was much higher than the 4.5% reported in Japan.² Therefore, neovascular AMD in Japanese and Asian patients has demographic features that differ much from that in Caucasian patients.

The higher proportion of PCV in Japanese patients helps to develop the new concept of a clinical type of neovascular AMD. Maruko and associates²⁰ reported 20 combined cases of PCV and typical AMD among 349 patients with neovascular AMD; these patients had a combination type of neovascular AMD, ie, one eye had PCV and the other eye had typical AMD. Although some cases could include the early stages of development in PCV or PCV unproved by ICG angiography, the combined cases might imply that both PCV and typical AMD are not independent and possibly overlap. Thus, it is sometimes difficult, even for retinal specialists, to distinguish PCV from typical AMD without ICG angiography.

Photodynamic therapy has already been established as an effective treatment for AMD,^21-26 especially PCV in recent years.^25,27-33 It is common knowledge in Japan that PDT is effective for PCV, because the JAT study — the first clinical trial in Japan of PDT for AMD — was significantly effective compared to other studies in western countries. This might seem to include PCV patients.^22-24 In addition, the efficacy of anti-VEGF therapy for PCV has not been determined yet.^5,32-34 Even today, PDT is still a useful and common therapy in Japan.

However, PDT has complications, such as sub- or intraretinal fluid accumulation after PDT as a temporary reaction and sudden severe vision loss because of subretinal bleeding.^35-38 ICG angiography-guided PDT is sometimes performed to reduce the laser-exposed area and associated adverse events. In Japan, a prospective multicenter study comparing the efficacy and safety of fluorescein and ICG angiography-guided PDT is now being conducted by the Ophthalmic PDT Study Group.

Recently, combination therapy with PDT and anti-VEGF therapy was reported by several groups.^33,39-43 The FOCUS study showed ranibizumab+PDT was more effective than PDT alone.³⁹ Combination therapy for PCV is expected to continue to reduce the frequency of treatments and the recurrence rates.

The natural course of RAP has poorer visual outcomes and a higher risk of bilateral neovascularization than typical AMD, and the treatment results of laser photocoagulation, surgical abrasion and monotherapy of PDT have not been adequate.^44-48 Because PDT is still a common therapy for AMD in Japan, as previously mentioned, many retinal specialists in Japan consider performing combination therapy to manage cases of RAP. Saito and associates^40,43 reported that combination therapy of bevacizumab and PDT for RAP maintained and improved visual acuity after six and 12 months follow-up. Although further large and long-term prospective randomized studies are needed, this result may indicate that combination therapy should be considered for RAP.

Neovascular AMD in Japanese and other Asian patients has different demographic features from those in white patients, such as the predominance of PCV, low frequency of RAP, and the combined cases of PCV and typical AMD. Although we understand the interethnic differences between east and west, we may consider PDT as one of the treatment options for patients with PCV or RAP in case of the poor response to anti-VEGF therapy. RP

REFERENCES

1. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina. 1990;10(1):1-8.
2. Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, Freund KB, Sorenson J, Orlock D, Borodoker N. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001;21(5):416-434.
3. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
4. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
5. Cho M, Barbazetto IA, Freund KB. Refractory neovascular age-related macular degeneration secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol. 2009;148(1):70-78.e1.
6. Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T. Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study. Br J Ophthalmol. 2001;85(10):1153-1157.
7. Kawasaki R, Wang JJ, Ji GJ, Taylor B, Oizumi T, Daimon M, Kato T, Kawata S, Kayama T, Tano Y, Mitchell P, Yamashita H, wong TY. Prevalence and risk factors for age-related macular degeneration in an adult Japanese population: the Funagata study. Ophthalmology. 2008;115(8):1376-1381, 1381.e1-2.
8. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-943.
9. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology. 1995;102(2):205-210.
10. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology. 1995;102(10):1450-1460.
11. Schachat AP, Hyman L, Leske MC, Connell AM, Wu SY. Features of age-related macular degeneration in a black population. The Barbados Eye Study Group. Arch Ophthalmol. 1995;113(6):728-735.
12. Miyazaki M, Kiyohara Y, Yoshida A, Iida M, Nose Y, Ishibashi T. The 5-year incidence and risk factors for age-related maculopathy in a general Japanese population: the Hisayama study. Invest Ophthalmol Vis Sci. 2005;46(6):1907-1910.
13. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;104(1):7-21.
14. Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology. 2002;109(6):1092-1097.
15. Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical Characteristics of Exudative Age-Related Macular Degeneration in Japanese Patients. Am J Ophthalmol. 2007;144(1):15-22.
16. Yannuzzi LA, Wong DW, Sforzolini BS, Goldbaum M, Tang KC, Spaide RF, Freund KB, Slakter JS, Guyer DR, Sorenson JA, Fisher Y, Maberley D, Orlock DA. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch Ophthalmol. 1999;117(11):1503-1510.
17. Sho K, Takahashi K, Yamada H, et al. Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics. Arch Ophthalmol. 2003;121(10):1392-1396.
18. Wen F, Chen C, Wu D, Li H. Polypoidal choroidal vasculopathy in elderly Chinese patients. Graefes Arch Clin Exp Ophthalmol. 2004;242(8):625-629.
19. Byeon SH, Lee SC, Oh HS, Kim SS, Koh HJ, Kwon OW. Incidence and clinical patterns of polypoidal choroidal vasculopathy in Korean patients. Jpn J Ophthalmol. 2008;52(1):57-62.
20. Maruko I, Iida T, Saito M, Nagayama D. Combined cases of polypoidal choroidal vasculopathy and typical age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2010;248(3):361-368.
21. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP Report 1. Arch Ophthalmol. 1999;117(10):1329-1345.
22. Japanese Age-Related Macular Degeneration Trial (JAT) Study Group. Japanese age-related macular degeneration trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Am J Ophthalmol. 2003;136(6):1049-1061.
23. Verteporfin Roundtable 2000 and 2001 Participants; Treatment of age-related macular degeneration with photodynamic therapy (TAP) study group principal investigators; Verteporfin in photodynamic therapy (VIP) study group principal investigators. Guidelines for using verteporfin (visudyne) in photodynamic therapy to treat choroidal neovascularization due to age-related macular degeneration and other causes. Retina. 2002;22(1):6-18.
24. Verteporfin Roundtable Participants. Guidelines for using verteporfin (Visudyne) in photodynamic therapy for choroidal neovascularization due to age-related macular degeneration and other causes: update. Retina. 2005;25(2):119-134.
25. Tano Y; Ophthalmic PDT Study Group. Guidelines for PDT in Japan. Ophthalmology. 2008;115(3):585-585.e6.
26. Quaranta M, Mauget-Faÿsse M, Coscas G. Exudative idiopathic polypoidal choroidal vasculopathy and photodynamic therapy with verteporfin. Am J Ophthalmol. 2002;134(2):277-280.
27. Spaide RF, Donsoff I, Lam DL, Yannuzzi LA, Jampol LM, Slakter J, Sorenson J, Freund KB. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy. Retina. 2002;22(5):529-535.
28. Chan WM, Lam DS, Lai TY, Liu DT, Li KK, Yao Y, Wong TH. Photodynamic therapy with verteporfin for symptomatic polypoidal choroidal vasculopathy: one-year results of a prospective case series. Ophthalmology. 2004;111(8):1576-1584.
29. Otani A, Sasahara M, Yodoi Y, Aikawa H, Tamura H, Tsujikawa A, Yoshimura N. Indocyanine green angiography: guided photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2007;44(1):7-14.
30. Akaza E, Mori R, Yuzawa M. Long-term results of photodynamic therapy of polypoidal choroidal vasculopathy. Retina. 2008;28(5):717-722.
31. Saito M, Iida T, Nagayama D. Photodynamic therapy with verteporfin for age-related macular degeneration or polypoidal choroidal vasculopathy: comparison of the presence of serous retinal pigment epithelial detachment. Br J Ophthalmol. 2008;92(12):1642-1647.
32. Gomi F, Sawa M, Sakaguchi H, Tsujikawa M, Oshima Y, Kamei M, Tano Y. Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008;92(1):70-73.
33. Lai TY, Chan WM, Liu DT, Luk FO, Lam DS. Intravitreal bevacizumab (Avastin) with or without photodynamic therapy for the treatment of polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008;92(5):661-666.
34. Kokame GT, Yeung L, Lai JC. Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: an Interim 6-month report. Br J Ophthalmol. 2009 Sep 22. [Epub ahead of print]
35. Schmidt-Erfurth U, Hasan T, Gragoudas E, Michaud N, Flotte TJ, Birngruber R. Vascular targeting in photodynamic occlusion of subretinal vessels. Ophthalmology. 1994;101(12):1953-1961.
36. Schmidt-Erfurth U, Laqua H, Schlötzer-Schrehard U, Viestenz A, Naumann GO. Histopathological changes following photodynamic therapy in human eyes. Arch Ophthalmol. 2002;120(6):835-844.
37. Rogers AH, Martidis A, Greenberg PB, Puliafito CA. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol. 2002;134(4):566-576.
38. Hirami Y, Tsujikawa A, Otani A, Yodoi Y, Aikawa H, Mandai M, Yoshimura N. Hemorrhagic complications after photodynamic therapy for polypoidal choroidal vasculopathy. Retina. 2007;27(3):335-341.
39. Antoszyk AN, Tuomi L, Chung CY, Singh A; FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol. 2008;145(5):862-874.
40. Saito M, Shiragami C, Shiraga F, Nagayama D, Iida T. Combined intravitreal bevacizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol. 2008;146(6):935-941.e1.
41. Kiss CG, Simader C, Michels S, Schmidt-Erfurth U. Combination of verteporfin photodynamic therapy and ranibizumab: effects on retinal anatomy, choroidal perfusion and visual function in the protect study. Br J Ophthalmol. 2008;92(12):1620-1627.
42. Kaiser PK; Registry of Visudyne AMD Therapy Writing Committee, Boyer DS, Garcia R, Hao Y, Hughes MS, Jabbour NM, Kaiser PK, Mieler W, Slakter JS, Samuel M, Tolentino MJ, Roth D, Sheidow T, Strong HA. Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2009;116(4):747-755.755.e1.
43. Saito M, Shiragami C, Shiraga F, Kano M, Iida T. Comparison of Intravitreal Triamcinolone Acetonide with Photodynamic Therapy and Intravitreal Bevacizumab with Photodynamic Therapy for Retinal Angiomatous Proliferation. Am J Ophthalmol. 2010;149(3):472-481.
44. Bottoni F, Massacesi A, Cigada M, Viola F, Musicco I, Staurenghi G. Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation. Arch Ophthalmol. 2005;123(12):1644-1650.
45. Slakter JS, Yannuzzi LA, Schneider U, Sorenson JA, Ciardella A, Guyer DR, Spaide R F, Freund KB, Orlock DA. Retinal choroidal anastomoses and occult choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2000;107(4):742-753.
46. Kuroiwa S, Arai J, Gaun S, Iida T, Yoshimura N.Rapidly progressive scar formation after transpupillary thermotherapy in retinal angiomatous proliferation. Retina. 2003;23(3):417-420.
47. Sakimoto S, Gomi F, Sakaguchi H, Tano Y.Recurrent retinal angiomatous proliferation after surgical ablation. Am J Ophthalmol. 2005;139(5):917-918.
48. Shiragami C, Iida T, Nagayama D, Baba T, Shiraga F.Recurrence after surgical ablation for retinal angiomatous proliferation. Retina. 2007;27(2):198-203.