- Email: [email protected]
Age-related macular degeneration: is polypoidal choroidal vasculopathy recognized and treated?
Age-related macular degeneration: Is polypoidal choroidal vasculopathy recognized and treated? Yufeng N. Chen, MD,* Robert G. Devenyi, MD,† Michael H. Brent, MD,† Peter J. Kertes, MD,† Kenneth T. Eng, MD,† Carol E. Schwartz, MD,† Radha P. Kohly, MD,† David R. Chow, MD,† David T. Wong, MD,† Alan R. Berger, MD,† Fil Altomare, MD,† Louis R. Giavedoni, MD,† Rajeev H. Muni, MD,† Alexander Soon, MD,‡ Patrick Yoo, MSc,§ Wai-Ching Lam, MD† ABSTRACT ● Objective: To assess how polypoidal choroidal vasculopathy (PCV) is recognized and treated, and to assess whether treatment outcomes are different between Chinese and Caucasian Canadian patients with age-related macular degeneration (AMD). Design: Retrospective chart review. Participants: 154 eyes from 135 Chinese patients and 2291 eyes from 1792 Caucasian patients who were newly diagnosed with either AMD or PCV and had more than 1 year of follow-up were included. Methods: All newly diagnosed AMD patients presenting to the Retina Service of 3 Toronto University Hospitals, between March 25, 2008, to September 30, 2014, were reviewed. Results: 10/154 eyes (6.5%) in Chinese Canadians and 16/2291 eyes (0.7%) in Caucasian Canadians were diagnosed as having PCV. Indocyanine green angiography (ICGA) was used to diagnose PCV in 20% of Chinese Canadians and 8.8% of Caucasian Canadians. Clinical practices with a larger percentage of Chinese patients were more likely to diagnose PCV in both Chinese (p ¼ 0.004) and Caucasian patients (p ¼ 0.03), were more likely to use photodynamic therapy (PDT) (p o 0.01), and had significantly greater central retinal thickness decrease (p o 0.001). Conclusion: Our study has shown that PCV is under-recognized in a Canadian population, and ICGA is underutilized. In clinical practices with a greater portion of Chinese patients, PCV is more often recognized and PDT is used more liberally.
Age-related macular degeneration (AMD) is a chronic disease that affects around 6.8% of Asians and 8.8% of Caucasians from age 40 to 79 years.1 Asians and Caucasians are different when it comes to AMD; the prevalence of polypoidal choroidal vasculopathy (PCV) is much higher in Asians than in Caucasians.2–6 Although PCV is present among 10.5%–25% of Chinese AMD patients, it is present among only 7.8%–8.4% of Caucasian AMD patients.2,4,5,7,8 PCV is often under-recognized and mislabelled as AMD, which can lead to inadequate treatment and worse clinical outcomes.9 In North America, where there are fewer Asian patients, PCV may be even more under-recognized. No studies to date have looked at the PCV diagnosis and treatment in a North American city. PCV is a unique subtype of AMD that responds differently to treatment. Although anti-vascular endothelial growth factors (anti-VEGF) are first-line treatments for AMD,10,11 the EVEREST study showed that, for patients with PCV, treatment with photodynamic therapy (PDT) alone or in combination with anti-VEGF had significantly better polyp regression.12 Other studies have also shown
that a combination of anti-VEGF with PDT in PCV patients results in better visual and central retinal thickness (CRT) outcomes.13,14 Although LAPTOP showed that PCV patients treated with PDT alone had worse visual and CRT outcomes compared with anti-VEGF alone, Kim and associates showed that PDT alone is inferior to a combination of anti-VEGF and PDT, suggesting that the best treatment for PCV is PDT and anti-VEGF combined.15,16 PCV patients treated with anti-VEGF monotherapy have worse visual outcomes than similarly treated AMD patients.17 Thus, if PCV lesions are not recognized, some patients may be inadequately treated with antiVEGF monotherapy, leading to worsening outcomes. Thus, it is important to assess the rate of PCV diagnosis in North America, and assess whether or not PCV patients are properly recognized and treated. The goal of this study is to assess the diagnosis of PCV in both Asians and Caucasians in a North American cohort, and how often the gold-standard test, indocyanine green angiography (ICGA), is used. This study also looks at how often the first-line therapy for PCV, which is a combination of PDT with anti-VEGF, is used.
& 2017 Published by Elsevier Inc on behalf of the Canadian Ophthalmological Society. http://dx.doi.org/10.1016/j.jcjo.2017.02.014 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
PCV and AMD in Chinese and Caucasians—Chen et al. METHODS Design
Institutional review board approval was obtained from the University Health Network, St. Michael’s Hospital, and Sunnybrook Health Sciences Centre to review patient data for this retrospective study. Informed consent was deemed to be not required. This study adheres to the tenets of the Declaration of Helsinki.
diagnosed as PCV (p ¼ 0.04). Out of these only 20% of the Chinese patients and 8.8% of Caucasian patients labelled as having PCV were verified with ICGA. Only 7.1% of the patients diagnosed with PCV received PDT combined with anti-VEGF, whereas all of them received anti-VEGF treatment. Of the patients, 23% diagnosed with PCV had received treatment with anti-VEGF before being diagnosed, and had a mean of 4 injections before being diagnosed.
Patient selection
Patient records were identified by billing entry for antiVEGF treatment from March 2008 to March 2014. From this list, patients meeting the inclusion and exclusion criteria were identified and information was collected. Patients were included in the study if they were labelled as having AMD or PCV, were 65 years or older, and were treatment naive before March 25, 2008. Patients were excluded if they had less than 1-year follow-up or had CNV from causes other than AMD or PCV. All AMD lesion subtypes and lesion sizes were eligible. Patients were classified as AMD or PCV through interpretation of either intravenous sodium fluorescein angiography (IVFA) or ICGA by their provider and recorded on the chart. To see whether practices with a greater proportion of Chinese patients perform differently from those practices with a lesser proportion of Chinese patients, we chose to do a subgroup analysis comparing practices with 410% versus those with o10% Chinese AMD patients. Because ethnicity information was not always available, SANGRA list of surnames, which has a sensitivity of 80.2% and specificity of 91.9% for Chinese patients, was used to classify the patients’ ethnicity.18
Baseline demographics
All baseline demographics were similar in the 2 ethnicities; however, mean age of first treatment (p o 0.001), incidence of myopia (p o 0.0001), male sex (p ¼ 0.04), incidence of myocardial infarctions (p ¼ 0.02), incidence of diabetic retinopathy (p ¼ 0.04), and incidence of BRVO (p ¼ 0.05) were all higher in Chinese Canadians than in Caucasian Canadians (see Table 1). Baseline visual acuity was also significantly worse in Chinese compared with Caucasian patients (20/175 vs 20/ 132, p ¼ 0.02). Visual acuity and CRT
Chinese and Caucasian patients both did not have significant change in vision from baseline to final visit (p ¼ 0.93, p ¼ 0.3) (see Table 2). The change in vision from baseline to last follow-up was not significantly different between Chinese and Caucasians patients (p ¼ 0.13). Both Chinese and Caucasian patients had significant decrease in CRT from baseline to final visit (p o 0.001, p o 0.001). The change in CRT was also not significantly different between the 2 ethnicities (p ¼ 0.71).
Data analysis
Treatment types
The t test was used to compare the means of the continuous measures between Chinese and Caucasians. Fisher’s exact test was used to assess the association between ethnicity and categorical measures. The differences between Chinese and Caucasians for changes in visual acuity and CRT are assessed using linear regression. The generalized estimating equation (GEE) method was used to account for correlation between the left and the right eyes of the same patient. Factors included in the linear analysis were ethnicity, followup time, age, sex, baseline visual acuity, baseline CRT, PDT use, percentage of Chinese patients in the physician’s practice, history of glaucoma, myopia, cataract, hypertension, diabetic retinopathy, diabetes, and cardiac disease. Confounders were adjusted for during comparisons.
For treatment, 5.1% of Chinese patients and 2.4% of Caucasian patients had PDT. Chinese patients were more
RESULTS PCV diagnosis and treatment
In this study, 10/154 eyes (6.5%) in Chinese Canadians and 16/2291 eyes (0.7%) in Caucasian Canadians were
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
Table 1—Patient demographics
Age, years Female, n (%) Baseline vision (Snellen) Baseline CRT (μm) Hypertension, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Stroke, n (%) Myocardial infarction, n (%) Depression, n (%) Hypothyroidism, n (%) Cataract, n (%) Diabetic retinopathy, n (%) Myopia, n (%) Glaucoma, n (%) BRAO, n (%) BRVO, n (%) CRVO, n (%) Ocular surgery, n (%)
Chinese
Caucasians
p
77 66 (49) 20/175 294 80 (59) 26 (19) 6 (4.4) 2 (1.5) 13 (9.6) 10 (7.4) 8 (5.9) 80 (59) 9 (6.7) 6 (4.4) 13 (9.6) 0 (0) 2 (1.5) 0 (0) 84 (62)
81 1039 (58) 20/132 296 950 (53) 389 (22) 116 (6.5) 23 (1.3) 308 (17) 11 (0.6) 188 (10.5) 1093 (61) 45 (2.5) 28 (1.6) 271 (15.1) 2 (0.1) 5 (0.3) 3 (0.2) 1057 (59)
o0.0001 0.04 0.02 0.86 0.21 0.43 0.41 0.84 0.02 0.87 0.09 0.46 0.04 o0.0001 0.07 0.71 0.05 0.56 0.72
CRT, central retinal thickness; BRAO, branch retinal artery occlusion; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion.
PCV and AMD in Chinese and Caucasians—Chen et al. Table 2—Treatment and treatment outcomes for Chinese and Caucasian patients
Baseline
Last Followup
Chinese (vision)
20/175
20/193
Caucasian (vision) Chinese (CRT, μm) Caucasian (CRT, μm) Chinese (PDT use) Caucasian (PDT use) Chinese (anti-VEGF 100 months) Caucasian (anti-VEGF 100 months)
20/132 294 296 n/a n/a n/a
20/151 249 254 n/a n/a n/a
n/a
n/a
Mean
p
lose 0.5 0.93 letters lose 2 letters 0.3 39.7 o0.001 30.6 o0.001 5.1% o0.001 2.4% 50.5 0.01 58.1
CRT, central retinal thickness; PDT, photodynamic therapy; anti-VEGF, anti-vascular endothelial growth factors.
likely to get PDT (p o 0.001). Only 3.1% of patients who received PDT were diagnosed with PCV; others were labelled as AMD refractory to treatment. Twenty-five percent of Caucasians and 12.5% of Chinese patients received PDT for PCV. The number of anti-VEGF injections per 100 month was significantly lower in Chinese than in Caucasian patients (50.5 vs 58.1, p ¼ 0.01) (see Table 2).
in CRT (p ¼ 0.02) and higher PDT use (p ¼ 0.02), but no significant difference in change in visual acuity (p ¼ 0.46) (see Table 3). Likewise, Caucasian patients treated at practices with 10% or more Chinese populations had a significantly greater decrease in CRT (p ¼ 0.2) and higher PDT use (p o 0.001), but change in visual acuity was not significantly different (p ¼ 0.46) (see Table 3). Factors influencing visual acuity, CRT outcomes, and number of anti-VEGF treatments needed
The only 2 factors found to influence change in visual acuity from baseline to last follow-up were age (estimate 0.007; CI 0.01 to 0.003) and baseline visual acuity (estimate 0.55; CI 0.5 to 0.6). Ethnicity (p ¼ 0.12) and follow-up time (p ¼ 0.19) did not make a difference in change in vision. CRT change was influenced by being female (11.8; CI 3.1 to 20.5), higher baseline CRT (0.75; CI 0.6 to 0.9), and worse baseline visual acuity (11.9; CI 3.4 to 20.5).
DISCUSSION Subgroup analysis by portion of practice consisting of Chinese patients
Of the retinal specialists, 2/13 had practices that included more than 10% Chinese patients. For these 2 practices, both baseline visual acuity and average followup time were similar between practices with 410% and o10% Chinese patients (p ¼ 0.10 and p ¼ 0.59, respectively). The rate of PCV diagnosis was significantly higher in these 2 practices compared with other practices (9.4% vs 0% diagnosis rate of PCV in Chinese patients, p ¼ 0.004; 1.3% vs 0.1% diagnosis rate of PCV in Caucasian patients, p ¼ 0.03). These 2 practices were also significantly more likely to use PDT (8.5% vs 2.1% usage, p o 0.001). The change in visual acuity from baseline to final was not significantly different between the 2 types of practices (p ¼ 0.2); however, change in CRT was (p o 0.001) (see Table 3). Chinese patients treated at practices with 410% Chinese populations had a significantly greater decrease
The prevalence of diagnosed PCV in our study for both Chinese and Caucasians was less than expected, 6.5% and 0.7%, respectively, compared with previous epidemiological studies, in which the incidence was around 20%– 30%.2,4,5 Similarly, the expected incidence of Caucasian patients with PCV is around 7%, whereas in this study only 0.7% were actually diagnosed.7,8 That the percent of undiagnosed PCV in Caucasians was greater than that in Chinese patients is perhaps attributed to the fact that physicians are more aware of PCV in Chinese patients. This result suggests that there might have been a significant underdiagnosis of PCV in Canada in both ethnic groups. Furthermore, out of those diagnosed as having PCV, only 20% of the Chinese PCV patients and 8.8% of Caucasian PCV patients were verified with ICGA, the gold standard for PCV diagnosis. This suggests an underutilization of ICGA in North America for PCV diagnosis. According to the baseline demographics, Chinese AMD patients in this study had greater percentage of males and
Table 3—Treatment outcome for all patients depending on composition of practice
Change in visual acuity for Chinese patients (letters) Change in CRT for Chinese patients (mm) PDT use in Chinese patients (%) Change in visual acuity for Caucasian patients (letters) Change in CRT for Caucasian patients (mm) PDT use in Caucasians patients (%) Change in visual acuity for overall group (letters) Change in CRT for overall group (mm) PDT use in overall group (%)
Practices with 410% Chinese Patients
Practices with o10% Chinese Patients
p
Gain 0.8 letters 66.3 5.2 Gain 0.7 letters 66.6 7.6 Gain 2 letters 41.3 8.5
Lose 0.6 letters 22.5 2 Lose 0.5 letters 23.6 2.1 Lose 2.7 letters 23.9 2.1
0.46 0.02 0.02 0.2 o0.01 o0.001 0.2 o0.001 o0.001
CRT, central retinal thickness; PDT, photodynamic therapy.
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
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PCV and AMD in Chinese and Caucasians—Chen et al. had significantly worse baseline vision compared with Caucasian AMD patients. PCV is known to be more prevalent in males.19,20 Baseline vision might be worse in Chinese patients for a variety of reasons. Chen et al. showed that Asian Americans had lower physician and medication costs and that they were more likely to visit the emergency department.2 Perhaps Chinese Canadians also do not use health care resources until their symptoms (i.e., vision) were worse and do not participate in regular checkups. This might also be the reason that diabetic retinopathy was more severe in Chinese Canadians even though the prevalence of diabetes was similar between the 2 populations. Clinical outcomes were not significantly different between Caucasians and Chinese patients in this study. Our study also showed that Chinese patients were more likely to receive PDT combined with anti-VEGF, and to receive ICGA to verify suspicion of PCV diagnosis. Interestingly, only 3.1% of the overall patients who received PDT were receiving it for PCV; the rest received PDT for refractory AMD. Hatz et al. showed that among patients not responding well to ranibizumab for the treatment of AMD, around 21.5% were actually PCV patients mislabelled as having AMD, and so a portion of the patients receiving PDT may actually had undiagnosed PCV.21 The clinical outcome of Asian and Caucasians in our cohort was similar likely because PCV is underrecognized in both ethnic groups. Our study showed that there was overall decrease in vision in both ethnicities over time; this was also demonstrated by the SEVEN-UP study, which showed that vision fell below baseline vision after year 4.22 The linear regression showed that the number of years on treatment did not seem to influence change in vision or change in CRT from baseline to last follow-up when other factors were controlled for.22 It, however, showed that the longer the patients were receiving treatment, the fewer the number of anti-VEGF treatments required over time, likely because many of the patients in this study were on a “treat and extend” dosing regimen. Physicians with a higher proportion of Chinese patients in their practices may be more cognizant of PCV and more inclined to use PDT. PCV was diagnosed at a higher rate for both Chinese and Caucasian AMD patients in practices with a greater proportion of Chinese patients, and both ethnicities were also more likely to receive PDT. Additionally, a greater proportion of patients had significantly greater decrease in CRT in practices with more Chinese AMD patients. The higher use of PDT might have contributed to the greater CRT decrease. The fact that greater reduction in CRT did not translate into better vision may be because there is often a delay in recognizing and treating. Tozer et al. have shown that the combination of PDT plus anti-VEGF therapy has been shown to improve visual outcome in AMD patients who were refractory to treatment; thus, PDT may play a role not
4
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
just in PCV but also in AMD not responding to monotherapy.23 However, since Tozer et al. used only IVFA for diagnosis, it is possible that a portion of the patients could have PCV and not treatment refractory AMD.23 One limitation of our study is lack of government funding for ICGA and PDT in Ontario, which could have contributed to the underutilization of both. Additionally, because of lack of government funding for ICGA, in a large number of PCV cases, the lesions were not verified by ICGA, which is the gold standard. This study suggests that there is a significant underdiagnosis of PCV in this study population. ICGA is also underutilized in the treatment of PCV, and PDT is likewise underutilized. PCV is more likely to be recognized in Chinese AMD patients compared with Caucasian AMD patients, and Chinese patients are also more likely to receive PDT. Further study using ICGA to confirm the diagnosis of patients suspected to have PCV and AMD patients refractory to anti-VEGF therapy will be helpful to provide a more accurate prevalence of PCV in our patient population. REFERENCES 1. Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular degeneration in Asians: a systematic review and metaanalysis. Ophthalmology. 2010;117:921-7. 2. Chen SJ, Cheng CY, Peng KL, et al. Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Invest Ophthalmol Vis Sci. 2008;49:3126-33. 3. You QS, Xu L, Yang H, et al. Five-year incidence of age-related macular degeneration: the Beijing Eye Study. Ophthalmology. 2012;119:2519-25. 4. Lee KY, Wong AL, Luk FO, Lai TY. Visual outcome of retinal angiomatous proliferation in Chinese patients following photodynamic therapy or direct laser photocoagulation. Hong Kong J Ophthalmol. 2009;13:5-8. 5. Liu Y, Wen F, Huang S, et al. Subtype lesions of neovascular agerelated macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol. 2007;245:1441-5. 6. Ciardella AP, Donsoff IM, Yannuzzi LA. Polypoidal choroidal vasculopathy. Ophthalmol Clin North Am. 2002;15:537-54. 7. Yannuzzi LA, Wong DW, Sforzolini BS, et al. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch Ophthalmol. 1999;117:1503-10. 8. Ladas ID, Rouvas AA, Moschos MM, Synodinos EE, Karagiannis DA, Koutsandrea CN. Polypoidal choroidal vasculopathy and exudative age-related macular degeneration in Greek population. Eye (Lond). 2004;18:455-9. 9. Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB, Orlock DA. The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol. 1997;115:478-85. 10. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116:57-65. e5 . 11. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-31. 12. 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;32:1453-64.
PCV and AMD in Chinese and Caucasians—Chen et al. 13. Saito M, Iida T, Kano M. Combined intravitreal ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. Retina. 2012;32:1272-9. 14. Lee YH, Lee EK, Shin KS, Lee KM, Kim JY. Intravitreal ranibizumab combined with verteporfin photodynamic therapy for treating polypoidal choroidal vasculopathy. Retina. 2011;31:1287-93. 15. 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. 16. Kim SJ, Yu HG. Efficacy of combined photodynamic therapy and intravitreal bevacizumab injection versus photodynamic therapy alone in polypoidal choroidal vasculopathy. Retina. 2011;31:1827-34. 17. Matsumiya W, Honda S, Kusuhara S, Tsukahara Y, Negi A. Effectiveness of intravitreal ranibizumab in exudative age-related macular degeneration (AMD): comparison between typical neovascular AMD and polypoidal choroidal vasculopathy over a 1 year follow-up. BMC Ophthalmol. 2013;13:10. 18. Shah BR, Chiu M, Amin S, Ramani M, Sadry S, Tu JV. Surname lists to identify South Asian and Chinese ethnicity from secondary data in Ontario, Canada: a validation study. BMC Med Res Methodol. 2010;10:42. 19. Kwok AK, Lai TY, Chan CW, Neoh EL, Lam DS. Polypoidal choroidal vasculopathy in Chinese patients. Br J Ophthalmol. 2002; 86:892-7. 20. Wen F, Chen C, Wu D, Li H. Polypoidal choroidal vasculopathy in elderly Chinese patients. Graefes Arch Clin Exp Ophthalmol. 2004; 242:625-9. 21. Hatz K, Prunte C. Polypoidal choroidal vasculopathy in Caucasian patients with presumed neovascular age-related macular degeneration and poor ranibizumab response. Br J Ophthalmol. 2014;98: 188-194. 22. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Group S-US. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120:2292-9. 23. Tozer K, Roller AB, Chong LP, et al. Combination therapy for neovascular age-related macular degeneration refractory to anti-
vascular endothelial growth factor agents. Ophthalmology. 2013; 120:2029-34.
Footnotes and Disclosure: Dr. Lam—consultant to Novartis and Bayer; research grants from Novartis and Bayer, advisory board of Novartis and Bayer. Dr. Muni—consulting honoraria from Novartis and Bayer. Dr. Wong—consultant to Alcon, Bausch & Lomb, Bayer, and Novartis; research grants from Alcon and Bayer. Dr. Berger— consultant to Bayer and Novartis; honoraria from Allergan, Bayer, and Novartis; research funds and grants from Novartis, Alcon, and Bayer; equity in Arctic Dx. Dr. Brent—research support from Novartis, Allergan, and Bayer; advisory board of Novartis, Bayer, and Alcon. Dr. Yaping Jin for being our consultant on statistical analysis. From the *University of Ottawa, Ottawa, Ont; †Department of Ophthalmology, University of Toronto, Toronto, Ont; ‡University of Western Ontario, London; §University of Melbourne, Melbourne, Australia. Presented at COS 2015 as an oral paper in Victoria, BC, June 20, 2015. Originally received Nov. 16, 2016. Accepted Feb. 14, 2017. Correspondence to Wai-Ching Lam, MD, Department of Ophthalmology and Vision Sciences, University of Toronto, 340 College street, Suite 400, Toronto, Ont. M5T 3A9; [email protected]
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
5
Age-related macular degeneration (AMD) is a chronic disease that affects around 6.8% of Asians and 8.8% of Caucasians from age 40 to 79 years.1 Asians and Caucasians are different when it comes to AMD; the prevalence of polypoidal choroidal vasculopathy (PCV) is much higher in Asians than in Caucasians.2–6 Although PCV is present among 10.5%–25% of Chinese AMD patients, it is present among only 7.8%–8.4% of Caucasian AMD patients.2,4,5,7,8 PCV is often under-recognized and mislabelled as AMD, which can lead to inadequate treatment and worse clinical outcomes.9 In North America, where there are fewer Asian patients, PCV may be even more under-recognized. No studies to date have looked at the PCV diagnosis and treatment in a North American city. PCV is a unique subtype of AMD that responds differently to treatment. Although anti-vascular endothelial growth factors (anti-VEGF) are first-line treatments for AMD,10,11 the EVEREST study showed that, for patients with PCV, treatment with photodynamic therapy (PDT) alone or in combination with anti-VEGF had significantly better polyp regression.12 Other studies have also shown
that a combination of anti-VEGF with PDT in PCV patients results in better visual and central retinal thickness (CRT) outcomes.13,14 Although LAPTOP showed that PCV patients treated with PDT alone had worse visual and CRT outcomes compared with anti-VEGF alone, Kim and associates showed that PDT alone is inferior to a combination of anti-VEGF and PDT, suggesting that the best treatment for PCV is PDT and anti-VEGF combined.15,16 PCV patients treated with anti-VEGF monotherapy have worse visual outcomes than similarly treated AMD patients.17 Thus, if PCV lesions are not recognized, some patients may be inadequately treated with antiVEGF monotherapy, leading to worsening outcomes. Thus, it is important to assess the rate of PCV diagnosis in North America, and assess whether or not PCV patients are properly recognized and treated. The goal of this study is to assess the diagnosis of PCV in both Asians and Caucasians in a North American cohort, and how often the gold-standard test, indocyanine green angiography (ICGA), is used. This study also looks at how often the first-line therapy for PCV, which is a combination of PDT with anti-VEGF, is used.
& 2017 Published by Elsevier Inc on behalf of the Canadian Ophthalmological Society. http://dx.doi.org/10.1016/j.jcjo.2017.02.014 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
PCV and AMD in Chinese and Caucasians—Chen et al. METHODS Design
Institutional review board approval was obtained from the University Health Network, St. Michael’s Hospital, and Sunnybrook Health Sciences Centre to review patient data for this retrospective study. Informed consent was deemed to be not required. This study adheres to the tenets of the Declaration of Helsinki.
diagnosed as PCV (p ¼ 0.04). Out of these only 20% of the Chinese patients and 8.8% of Caucasian patients labelled as having PCV were verified with ICGA. Only 7.1% of the patients diagnosed with PCV received PDT combined with anti-VEGF, whereas all of them received anti-VEGF treatment. Of the patients, 23% diagnosed with PCV had received treatment with anti-VEGF before being diagnosed, and had a mean of 4 injections before being diagnosed.
Patient selection
Patient records were identified by billing entry for antiVEGF treatment from March 2008 to March 2014. From this list, patients meeting the inclusion and exclusion criteria were identified and information was collected. Patients were included in the study if they were labelled as having AMD or PCV, were 65 years or older, and were treatment naive before March 25, 2008. Patients were excluded if they had less than 1-year follow-up or had CNV from causes other than AMD or PCV. All AMD lesion subtypes and lesion sizes were eligible. Patients were classified as AMD or PCV through interpretation of either intravenous sodium fluorescein angiography (IVFA) or ICGA by their provider and recorded on the chart. To see whether practices with a greater proportion of Chinese patients perform differently from those practices with a lesser proportion of Chinese patients, we chose to do a subgroup analysis comparing practices with 410% versus those with o10% Chinese AMD patients. Because ethnicity information was not always available, SANGRA list of surnames, which has a sensitivity of 80.2% and specificity of 91.9% for Chinese patients, was used to classify the patients’ ethnicity.18
Baseline demographics
All baseline demographics were similar in the 2 ethnicities; however, mean age of first treatment (p o 0.001), incidence of myopia (p o 0.0001), male sex (p ¼ 0.04), incidence of myocardial infarctions (p ¼ 0.02), incidence of diabetic retinopathy (p ¼ 0.04), and incidence of BRVO (p ¼ 0.05) were all higher in Chinese Canadians than in Caucasian Canadians (see Table 1). Baseline visual acuity was also significantly worse in Chinese compared with Caucasian patients (20/175 vs 20/ 132, p ¼ 0.02). Visual acuity and CRT
Chinese and Caucasian patients both did not have significant change in vision from baseline to final visit (p ¼ 0.93, p ¼ 0.3) (see Table 2). The change in vision from baseline to last follow-up was not significantly different between Chinese and Caucasians patients (p ¼ 0.13). Both Chinese and Caucasian patients had significant decrease in CRT from baseline to final visit (p o 0.001, p o 0.001). The change in CRT was also not significantly different between the 2 ethnicities (p ¼ 0.71).
Data analysis
Treatment types
The t test was used to compare the means of the continuous measures between Chinese and Caucasians. Fisher’s exact test was used to assess the association between ethnicity and categorical measures. The differences between Chinese and Caucasians for changes in visual acuity and CRT are assessed using linear regression. The generalized estimating equation (GEE) method was used to account for correlation between the left and the right eyes of the same patient. Factors included in the linear analysis were ethnicity, followup time, age, sex, baseline visual acuity, baseline CRT, PDT use, percentage of Chinese patients in the physician’s practice, history of glaucoma, myopia, cataract, hypertension, diabetic retinopathy, diabetes, and cardiac disease. Confounders were adjusted for during comparisons.
For treatment, 5.1% of Chinese patients and 2.4% of Caucasian patients had PDT. Chinese patients were more
RESULTS PCV diagnosis and treatment
In this study, 10/154 eyes (6.5%) in Chinese Canadians and 16/2291 eyes (0.7%) in Caucasian Canadians were
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
Table 1—Patient demographics
Age, years Female, n (%) Baseline vision (Snellen) Baseline CRT (μm) Hypertension, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Stroke, n (%) Myocardial infarction, n (%) Depression, n (%) Hypothyroidism, n (%) Cataract, n (%) Diabetic retinopathy, n (%) Myopia, n (%) Glaucoma, n (%) BRAO, n (%) BRVO, n (%) CRVO, n (%) Ocular surgery, n (%)
Chinese
Caucasians
p
77 66 (49) 20/175 294 80 (59) 26 (19) 6 (4.4) 2 (1.5) 13 (9.6) 10 (7.4) 8 (5.9) 80 (59) 9 (6.7) 6 (4.4) 13 (9.6) 0 (0) 2 (1.5) 0 (0) 84 (62)
81 1039 (58) 20/132 296 950 (53) 389 (22) 116 (6.5) 23 (1.3) 308 (17) 11 (0.6) 188 (10.5) 1093 (61) 45 (2.5) 28 (1.6) 271 (15.1) 2 (0.1) 5 (0.3) 3 (0.2) 1057 (59)
o0.0001 0.04 0.02 0.86 0.21 0.43 0.41 0.84 0.02 0.87 0.09 0.46 0.04 o0.0001 0.07 0.71 0.05 0.56 0.72
CRT, central retinal thickness; BRAO, branch retinal artery occlusion; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion.
PCV and AMD in Chinese and Caucasians—Chen et al. Table 2—Treatment and treatment outcomes for Chinese and Caucasian patients
Baseline
Last Followup
Chinese (vision)
20/175
20/193
Caucasian (vision) Chinese (CRT, μm) Caucasian (CRT, μm) Chinese (PDT use) Caucasian (PDT use) Chinese (anti-VEGF 100 months) Caucasian (anti-VEGF 100 months)
20/132 294 296 n/a n/a n/a
20/151 249 254 n/a n/a n/a
n/a
n/a
Mean
p
lose 0.5 0.93 letters lose 2 letters 0.3 39.7 o0.001 30.6 o0.001 5.1% o0.001 2.4% 50.5 0.01 58.1
CRT, central retinal thickness; PDT, photodynamic therapy; anti-VEGF, anti-vascular endothelial growth factors.
likely to get PDT (p o 0.001). Only 3.1% of patients who received PDT were diagnosed with PCV; others were labelled as AMD refractory to treatment. Twenty-five percent of Caucasians and 12.5% of Chinese patients received PDT for PCV. The number of anti-VEGF injections per 100 month was significantly lower in Chinese than in Caucasian patients (50.5 vs 58.1, p ¼ 0.01) (see Table 2).
in CRT (p ¼ 0.02) and higher PDT use (p ¼ 0.02), but no significant difference in change in visual acuity (p ¼ 0.46) (see Table 3). Likewise, Caucasian patients treated at practices with 10% or more Chinese populations had a significantly greater decrease in CRT (p ¼ 0.2) and higher PDT use (p o 0.001), but change in visual acuity was not significantly different (p ¼ 0.46) (see Table 3). Factors influencing visual acuity, CRT outcomes, and number of anti-VEGF treatments needed
The only 2 factors found to influence change in visual acuity from baseline to last follow-up were age (estimate 0.007; CI 0.01 to 0.003) and baseline visual acuity (estimate 0.55; CI 0.5 to 0.6). Ethnicity (p ¼ 0.12) and follow-up time (p ¼ 0.19) did not make a difference in change in vision. CRT change was influenced by being female (11.8; CI 3.1 to 20.5), higher baseline CRT (0.75; CI 0.6 to 0.9), and worse baseline visual acuity (11.9; CI 3.4 to 20.5).
DISCUSSION Subgroup analysis by portion of practice consisting of Chinese patients
Of the retinal specialists, 2/13 had practices that included more than 10% Chinese patients. For these 2 practices, both baseline visual acuity and average followup time were similar between practices with 410% and o10% Chinese patients (p ¼ 0.10 and p ¼ 0.59, respectively). The rate of PCV diagnosis was significantly higher in these 2 practices compared with other practices (9.4% vs 0% diagnosis rate of PCV in Chinese patients, p ¼ 0.004; 1.3% vs 0.1% diagnosis rate of PCV in Caucasian patients, p ¼ 0.03). These 2 practices were also significantly more likely to use PDT (8.5% vs 2.1% usage, p o 0.001). The change in visual acuity from baseline to final was not significantly different between the 2 types of practices (p ¼ 0.2); however, change in CRT was (p o 0.001) (see Table 3). Chinese patients treated at practices with 410% Chinese populations had a significantly greater decrease
The prevalence of diagnosed PCV in our study for both Chinese and Caucasians was less than expected, 6.5% and 0.7%, respectively, compared with previous epidemiological studies, in which the incidence was around 20%– 30%.2,4,5 Similarly, the expected incidence of Caucasian patients with PCV is around 7%, whereas in this study only 0.7% were actually diagnosed.7,8 That the percent of undiagnosed PCV in Caucasians was greater than that in Chinese patients is perhaps attributed to the fact that physicians are more aware of PCV in Chinese patients. This result suggests that there might have been a significant underdiagnosis of PCV in Canada in both ethnic groups. Furthermore, out of those diagnosed as having PCV, only 20% of the Chinese PCV patients and 8.8% of Caucasian PCV patients were verified with ICGA, the gold standard for PCV diagnosis. This suggests an underutilization of ICGA in North America for PCV diagnosis. According to the baseline demographics, Chinese AMD patients in this study had greater percentage of males and
Table 3—Treatment outcome for all patients depending on composition of practice
Change in visual acuity for Chinese patients (letters) Change in CRT for Chinese patients (mm) PDT use in Chinese patients (%) Change in visual acuity for Caucasian patients (letters) Change in CRT for Caucasian patients (mm) PDT use in Caucasians patients (%) Change in visual acuity for overall group (letters) Change in CRT for overall group (mm) PDT use in overall group (%)
Practices with 410% Chinese Patients
Practices with o10% Chinese Patients
p
Gain 0.8 letters 66.3 5.2 Gain 0.7 letters 66.6 7.6 Gain 2 letters 41.3 8.5
Lose 0.6 letters 22.5 2 Lose 0.5 letters 23.6 2.1 Lose 2.7 letters 23.9 2.1
0.46 0.02 0.02 0.2 o0.01 o0.001 0.2 o0.001 o0.001
CRT, central retinal thickness; PDT, photodynamic therapy.
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PCV and AMD in Chinese and Caucasians—Chen et al. had significantly worse baseline vision compared with Caucasian AMD patients. PCV is known to be more prevalent in males.19,20 Baseline vision might be worse in Chinese patients for a variety of reasons. Chen et al. showed that Asian Americans had lower physician and medication costs and that they were more likely to visit the emergency department.2 Perhaps Chinese Canadians also do not use health care resources until their symptoms (i.e., vision) were worse and do not participate in regular checkups. This might also be the reason that diabetic retinopathy was more severe in Chinese Canadians even though the prevalence of diabetes was similar between the 2 populations. Clinical outcomes were not significantly different between Caucasians and Chinese patients in this study. Our study also showed that Chinese patients were more likely to receive PDT combined with anti-VEGF, and to receive ICGA to verify suspicion of PCV diagnosis. Interestingly, only 3.1% of the overall patients who received PDT were receiving it for PCV; the rest received PDT for refractory AMD. Hatz et al. showed that among patients not responding well to ranibizumab for the treatment of AMD, around 21.5% were actually PCV patients mislabelled as having AMD, and so a portion of the patients receiving PDT may actually had undiagnosed PCV.21 The clinical outcome of Asian and Caucasians in our cohort was similar likely because PCV is underrecognized in both ethnic groups. Our study showed that there was overall decrease in vision in both ethnicities over time; this was also demonstrated by the SEVEN-UP study, which showed that vision fell below baseline vision after year 4.22 The linear regression showed that the number of years on treatment did not seem to influence change in vision or change in CRT from baseline to last follow-up when other factors were controlled for.22 It, however, showed that the longer the patients were receiving treatment, the fewer the number of anti-VEGF treatments required over time, likely because many of the patients in this study were on a “treat and extend” dosing regimen. Physicians with a higher proportion of Chinese patients in their practices may be more cognizant of PCV and more inclined to use PDT. PCV was diagnosed at a higher rate for both Chinese and Caucasian AMD patients in practices with a greater proportion of Chinese patients, and both ethnicities were also more likely to receive PDT. Additionally, a greater proportion of patients had significantly greater decrease in CRT in practices with more Chinese AMD patients. The higher use of PDT might have contributed to the greater CRT decrease. The fact that greater reduction in CRT did not translate into better vision may be because there is often a delay in recognizing and treating. Tozer et al. have shown that the combination of PDT plus anti-VEGF therapy has been shown to improve visual outcome in AMD patients who were refractory to treatment; thus, PDT may play a role not
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just in PCV but also in AMD not responding to monotherapy.23 However, since Tozer et al. used only IVFA for diagnosis, it is possible that a portion of the patients could have PCV and not treatment refractory AMD.23 One limitation of our study is lack of government funding for ICGA and PDT in Ontario, which could have contributed to the underutilization of both. Additionally, because of lack of government funding for ICGA, in a large number of PCV cases, the lesions were not verified by ICGA, which is the gold standard. This study suggests that there is a significant underdiagnosis of PCV in this study population. ICGA is also underutilized in the treatment of PCV, and PDT is likewise underutilized. PCV is more likely to be recognized in Chinese AMD patients compared with Caucasian AMD patients, and Chinese patients are also more likely to receive PDT. Further study using ICGA to confirm the diagnosis of patients suspected to have PCV and AMD patients refractory to anti-VEGF therapy will be helpful to provide a more accurate prevalence of PCV in our patient population. REFERENCES 1. Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular degeneration in Asians: a systematic review and metaanalysis. Ophthalmology. 2010;117:921-7. 2. Chen SJ, Cheng CY, Peng KL, et al. Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Invest Ophthalmol Vis Sci. 2008;49:3126-33. 3. You QS, Xu L, Yang H, et al. Five-year incidence of age-related macular degeneration: the Beijing Eye Study. Ophthalmology. 2012;119:2519-25. 4. Lee KY, Wong AL, Luk FO, Lai TY. Visual outcome of retinal angiomatous proliferation in Chinese patients following photodynamic therapy or direct laser photocoagulation. Hong Kong J Ophthalmol. 2009;13:5-8. 5. Liu Y, Wen F, Huang S, et al. Subtype lesions of neovascular agerelated macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol. 2007;245:1441-5. 6. Ciardella AP, Donsoff IM, Yannuzzi LA. Polypoidal choroidal vasculopathy. Ophthalmol Clin North Am. 2002;15:537-54. 7. Yannuzzi LA, Wong DW, Sforzolini BS, et al. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch Ophthalmol. 1999;117:1503-10. 8. Ladas ID, Rouvas AA, Moschos MM, Synodinos EE, Karagiannis DA, Koutsandrea CN. Polypoidal choroidal vasculopathy and exudative age-related macular degeneration in Greek population. Eye (Lond). 2004;18:455-9. 9. Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB, Orlock DA. The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol. 1997;115:478-85. 10. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116:57-65. e5 . 11. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-31. 12. 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;32:1453-64.
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Footnotes and Disclosure: Dr. Lam—consultant to Novartis and Bayer; research grants from Novartis and Bayer, advisory board of Novartis and Bayer. Dr. Muni—consulting honoraria from Novartis and Bayer. Dr. Wong—consultant to Alcon, Bausch & Lomb, Bayer, and Novartis; research grants from Alcon and Bayer. Dr. Berger— consultant to Bayer and Novartis; honoraria from Allergan, Bayer, and Novartis; research funds and grants from Novartis, Alcon, and Bayer; equity in Arctic Dx. Dr. Brent—research support from Novartis, Allergan, and Bayer; advisory board of Novartis, Bayer, and Alcon. Dr. Yaping Jin for being our consultant on statistical analysis. From the *University of Ottawa, Ottawa, Ont; †Department of Ophthalmology, University of Toronto, Toronto, Ont; ‡University of Western Ontario, London; §University of Melbourne, Melbourne, Australia. Presented at COS 2015 as an oral paper in Victoria, BC, June 20, 2015. Originally received Nov. 16, 2016. Accepted Feb. 14, 2017. Correspondence to Wai-Ching Lam, MD, Department of Ophthalmology and Vision Sciences, University of Toronto, 340 College street, Suite 400, Toronto, Ont. M5T 3A9; [email protected]
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