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Real-world cost-effectiveness of anti-VEGF monotherapy and combination therapy for the treatment of polypoidal choroidal vasculopathy



For patients with polypoidal choroidal vasculopathy (PCV), intravitreal anti-vascular endothelial growth factor (anti-VEGF) combination therapy has been shown to be cost-saving relative to monotherapy in a clinical trial setting. However, whether this also applies to real-world settings is unclear. We aim to compare the real-world functional outcomes and cost-effectiveness of intravitreal anti-VEGF combination therapy relative to monotherapy, to investigate whether combination therapy is truly cost-saving.


We used a Markov model to simulate a hypothetical cohort of PCV patients treated at Singapore National Eye Centre. Model parameters were informed by coarsened exact matched estimates of a two-year retrospective study of patients who initiated treatment in 2015. Treatment options included intravitreal aflibercept, bevacizumab, or ranibizumab, as monotherapy or in combination with full-fluence verteporfin photodynamic therapy.


The two-year logMAR letters gains were significant for combination therapy ( + 10.6, P = 0.006) but not monotherapy (−2.2, P = 0.459). Over 20 years, a PCV patient would cost the health system SGD 48,790 under monotherapy and SGD 61,020 under combination therapy. Quality-adjusted life-years (QALYs) were estimated to be 7.41 for monotherapy and 7.80 for combination therapy. The incremental cost-effectiveness ratio of combination therapy was SGD 31,460/QALY, which is less than the common willingness-to-pay threshold of per capita gross domestic product of Singapore (SGD 88,990/QALY). Sensitivity analysis showed that combination therapy remained incrementally cost-effective, but not cost-saving.


Our study shows that combination therapy is good value for money but is likely to increase costs when applied in real-world settings.

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Fig. 1: Markov Model Structure.


  1. Jordan-Yu JM, Teo K, Fan Q, Gana JC, Leopando AK, Nunes S, et al. Phenotypic and genetic variations between Asian and Caucasian polypoidal choroidal vasculopathy. Br J Ophthalmol. 2020.

  2. Cheung CMG, Lai TYY, Teo K, Ruamviboonsuk P, Chen SJ, Kim JE, et al. Polypoidal choroidal vasculopathy: consensus nomenclature and non-indocyanine green angiograph diagnostic criteria from the Asia-Pacific ocular imaging society PCV workgroup. Ophthalmology. 2020;128:443–52.

    Article  Google Scholar 

  3. Cheung CMG, Lai TYY, Ruamviboonsuk P, Chen SJ, Chen Y, Freund KB, et al. Polypoidal choroidal vasculopathy: definition, pathogenesis, diagnosis, and management. Ophthalmology 2018;125:708–24.

    Article  Google Scholar 

  4. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina 2012;32:1–8.

    PubMed  Google Scholar 

  5. Cheung GCM, Lai TYY, Gomi F, Ruamviboonsuk P, Koh A, Lee WK. Anti-VEGF therapy for neovascular AMD and polypoidal choroidal vasculopathy. Asia-Pacific J Ophthalmol. 2017;6:527–34.

    CAS  Google Scholar 

  6. Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, 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.

    CAS  Article  Google Scholar 

  7. Lim TH, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, et al. Comparison of Ranibizumab with or without Verteporfin Photodynamic therapy for polypoidal choroidal vasculopathy: the EVEREST II randomized clinical trial. JAMA Ophthalmol. 2020;138:935–42.

    Article  Google Scholar 

  8. Lee WK, Iida T, Ogura Y, Chen SJ, Wong TY, Mitchell P, et al. Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET study: a randomized clinical trial. JAMA Ophthalmol. 2018;136:786–93.

    Article  Google Scholar 

  9. Wong TY, Ogura Y, Lee WK, Iida T, Chen SJ, Mitchell P, et al. Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy: 2-year results of the PLANET Study. Am J Ophthalmol. 2019;204:80–9.

    CAS  Article  Google Scholar 

  10. Chan WM, Lam DS, Lai TY, Liu DT, Li KK, Yao Y, et al. Photodynamic therapy with verteporfin for symptomatic polypoidal choroidal vasculopathy: one-year results of a prospective case series. Ophthalmology 2004;111:1576–84.

    Article  Google Scholar 

  11. Spaide RF, Donsoff I, Lam DL, Yannuzzi LA, Jampol LM, Slakter J, et al. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy. 2002. Retina 2012;32:529–35. Suppl 1

    Article  Google Scholar 

  12. Doble B, Finkelstein EA, Tian Y, Saxena N, Patil S, Wong TY, et al. Cost-effectiveness of intravitreal Ranibizumab With verteporfin photodynamic therapy compared with ranibizumab monotherapy for patients with polypoidal choroidal vasculopathy. JAMA Ophthalmol. 2020;138:251–9.

    Article  Google Scholar 

  13. Fenner BJ, Ting DSW, Tan ACS, Teo K, Chan CM, Mathur R, et al. Real-world treatment outcomes of age-related macular degeneration and polypoidal choroidal vasculopathy in Asians. Ophthalmol Retin. 2020;4:403–14.

    Article  Google Scholar 

  14. Mehta H, Tufail A, Daien V, Lee AY, Nguyen V, Ozturk M, et al. Real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors. Prog Retin Eye Res. 2018;65:127–46.

    CAS  Article  Google Scholar 

  15. Finger RP, Puth MT, Schmid M, Barthelmes D, Guymer RH, Gillies M, Lifetime outcomes of anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration. JAMA Ophthalmol. 2020;138:1234–40.

  16. Iacus SM, King G, Porro G Causal inference without balance checking: Coarsened exact matching. Political analysis. 2012:1–24.

  17. StataCorp LLC. Stata Statistical Software. College Station, TX 2017.

  18. TreeAge Software. TreeAge Pro. Williamstown, MA 2020.

  19. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated health economic evaluation reporting standards (CHEERS)—explanation and elaboration: a report of the ispor health economic evaluation publication guidelines good reporting practices task force. Value Health. 2013;16:231–50.

    Article  Google Scholar 

  20. Koh A, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, et al. Efficacy and safety of Ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: a randomized clinical trial. JAMA Ophthalmol. 2017;135:1206–13.

    Article  Google Scholar 

  21. Singapore Department of Statistics. Complete Life Tables 2015-2016 for Singapore Resident Population 2017. Available from:

  22. Agency for Care Effectiveness. Drug Evaluation Methods and Process Guide 2019. Available from:

  23. Miyata M, Ooto S, Yamashiro K, Tamura H, Hata M, Ueda-Arakawa N, et al. Five-year visual outcomes after anti-VEGF therapy with or without photodynamic therapy for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2019;103:617–22.

  24. Wataru K, Sugiyama A, Yoneyama S, Matsubara M, Fukuda Y, Parikh R, et al. Five-year outcomes of photodynamic therapy combined with intravitreal injection of ranibizumab or aflibercept for polypoidal choroidal vasculopathy. PLoS One. 2020;15:e0229231.

    CAS  Article  Google Scholar 

  25. Koh A, Lai TYY, Wei WB, Mori R, Wakiyama H, Park KH, et al. Real-world effectiveness and safety of ranibizumab treatment in patients with and without polypoidal choroidal vasculopathy: twelve-month results from the luminous study. Retina 2020;40:1529–39.

    CAS  Article  Google Scholar 

  26. Group CR, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl J Med. 2011;364:1897–908.

    Article  Google Scholar 

  27. Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Awh CC, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the score2 randomized clinical trial. JAMA 2017;317:2072–87.

    CAS  Article  Google Scholar 

  28. Hykin P, Prevost AT, Vasconcelos JC, Murphy C, Kelly J, Ramu J, et al. Clinical effectiveness of intravitreal therapy with ranibizumab vs aflibercept vs bevacizumab for macular edema secondary to central retinal vein occlusion: a randomized clinical trial. JAMA Ophthalmol. 2019;137:1256–64.

    Article  Google Scholar 

  29. Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from Protocol T. Curr Opin Ophthalmol. 2017;28:636–43.

    Article  Google Scholar 

  30. Deaton A, Cartwright N. Understanding and misunderstanding randomized controlled trials. Soc Sci Med. 2018;210:2–21.

    Article  Google Scholar 

  31. Bro T, Derebecka M, Jørstad ØK, Grzybowski A. Off-label use of bevacizumab for wet age-related macular degeneration in Europe. Graefes Arch Clin Exp Ophthalmol. 2020;258:503–11.

    Article  Google Scholar 

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We thank Wee Siang Tay and Wei Han Melvin Wong for excellent research assistance.


This work was supported by Duke-NUS Medical School and Singapore Eye Research Institute.

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Authors and Affiliations



CMGC and EAF contributed to the study design. BJF contributed to data acquisition. JC, EAF, BJF and CMGC contributed to analysis and interpretation of results. JC and BJF drafted the manuscript with critical input from EAF, KYCT and CMGC. All authors read and approved the final manuscript.

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Correspondence to Junxing Chay.

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The authors declare no competing interests.

Ethics approval statement

This research was conducted in accordance with the Declaration of Helsinki and the local Institutional Review Board (studies 2009/788/A and R697/47/2009). Patients’ individual informed consent was exempted due to the retrospective nature of the study and use of anonymized clinical data. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

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Chay, J., Fenner, B.J., Finkelstein, E.A. et al. Real-world cost-effectiveness of anti-VEGF monotherapy and combination therapy for the treatment of polypoidal choroidal vasculopathy. Eye (2021).

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