Changing Reimbursement Criteria on Anti-VEGF Treatment Patterns Among Wet Age-Related Macular Degeneration and Diabetic Macular Edema Patients: An Interrupted Time Series Analysis

Document Type : Original Article


1 School of Pharmacy, National Taiwan University, Taipei, Taiwan

2 Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

3 Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan

4 Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan

5 Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

6 Taipei Municipal Gan-Dau Hospital (Managed by Taipei Veterans General Hospital), Taipei, Taiwan


To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan.


An interrupted time series analysis (ITSA) was performed using Taiwan’s National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection.


The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes.


This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.


  1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116. doi:1016/s2214-109x(13)70145-1
  2. Huang EJ, Wu SH, Lai CH, et al. Prevalence and risk factors for age-related macular degeneration in the elderly Chinese population in south-western Taiwan: the Puzih eye study. Eye (Lond). 2014;28(6):705-714. doi:1038/eye.2014.55
  3. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564. doi:2337/dc11-1909
  4. Klaver CC, Wolfs RC, Vingerling JR, Hofman A, de Jong PT. Age-specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol. 1998;116(5):653-658. doi:1001/archopht.116.5.653
  5. Bourne RR, Stevens GA, White RA, et al. Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health. 2013;1(6):e339-e349. doi:1016/s2214-109x(13)70113-x
  6. Moshfeghi AA, Lanitis T, Kropat G, et al. Social cost of blindness due to AMD and diabetic retinopathy in the United States in 2020. Ophthalmic Surg Lasers Imaging Retina. 2020;51(4):S6-S14. doi:3928/23258160-20200401-01
  7. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern®. Ophthalmology. 2020;127(1):P1-P65. doi:1016/j.ophtha.2019.09.024
  8. International Diabetes Federation. Clinical Practice Recommendations for Managing Diabetic Macular Edema.
  9. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. doi:1016/j.ophtha.2011.01.031
  10. Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: a randomized controlled trial. Adv Ther. 2020;37(3):1173-1187. doi:1007/s12325-020-01236-x
  11. Tsai MJ, Hsieh YT, Peng YJ. Real-life experience of ranibizumab for diabetic macular edema in Taiwan. Int Ophthalmol. 2019;39(7):1511-1522. doi:1007/s10792-018-0970-7
  12. Wu WC, Chen JT, Tsai CY, et al. A 12-month, prospective, observational study of ranibizumab in treatment-naïve Taiwanese patients with neovascular age-related macular degeneration: the RACER study. BMC Ophthalmol. 2020;20(1):462. doi:1186/s12886-020-01715-3
  13. Lai TT, Hsieh YT, Yang CM, Ho TC, Yang CH. Effect of reimbursement policy on visual outcomes in patients with diabetic macular edema treated with ranibizumab. Retina. 2020;40(11):2191-2197. doi:1097/iae.0000000000002716
  14. Cheung GC, Yoon YH, Chen LJ, et al. Diabetic macular oedema: evidence-based treatment recommendations for Asian countries. Clin Exp Ophthalmol. 2018;46(1):75-86. doi:1111/ceo.12999
  15. National Health Insurance Administration.
  16. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27(4):299-309. doi:1046/j.1365-2710.2002.00430.x
  17. Hsiao FY, Yang CL, Huang YT, Huang WF. Using Taiwan's National Health Insurance research database for pharmacoepidemiology research. J Food Drug Anal. 2007;15(2):99-108. doi:38212/2224-6614.2426
  18. Chen Y, Huang ST, Hsu TC, Peng LN, Hsiao FY, Chen LK. Detecting suspected prescribing cascades by prescription sequence symmetry analysis of nationwide real-world data. J Am Med Dir Assoc. 2022;23(3):468-474.e6. doi:1016/j.jamda.2021.06.035
  19. Hsu WH, Huang ST, Lu WH, Wen YW, Chen LK, Hsiao FY. Impact of multiple prescriptions with anticholinergic properties on adverse clinical outcomes in the elderly: a longitudinal cohort study in Taiwan. Clin Pharmacol Ther. 2021;110(4):966-974. doi:1002/cpt.2217
  20. Chen WW, Lin CW, Huang WI, Chao PH, Gau CS, Hsiao FY. Using real-world evidence for pharmacovigilance and drug safety-related decision making by a resource-limited health authority: 10 years of experience in Taiwan. Pharmacoepidemiol Drug Saf. 2020;29(11):1402-1413. doi:1002/pds.5084
  21. Meng LC, Huang ST, Chen HM, Hashmi AZ, Hsiao FY, Chen LK. Health care utilization and potentially preventable adverse outcomes of high-need, high-cost middle-aged and older adults: needs for integrated care models with life-course approach. Arch Gerontol Geriatr. 2023;109:104956. doi:1016/j.archger.2023.104956
  22. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:1016/0021-9681(87)90171-8
  23. Hudson J, Fielding S, Ramsay CR. Methodology and reporting characteristics of studies using interrupted time series design in healthcare. BMC Med Res Methodol. 2019;19(1):137. doi:1186/s12874-019-0777-x
  24. Penfold RB, Zhang F. Use of interrupted time series analysis in evaluating health care quality improvements. Acad Pediatr. 2013;13(6 Suppl):S38-S44. doi:1016/j.acap.2013.08.002
  25. Sheu SJ, Cheng CK, Kuo HK, et al. Treatment patterns in diabetic macular edema in Taiwan: a retrospective chart review. Clin Ophthalmol. 2018;12:2189-2198. doi:2147/opth.s170089
  26. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. doi:1016/j.ophtha.2011.12.039
  27. Curtis LH, Hammill BG, Qualls LG, et al. Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 Medicare beneficiaries. Am J Ophthalmol. 2012;153(6):1116-1124.e1. doi:1016/j.ajo.2011.11.032
  28. Lee WA, Shao SC, Liao TC, Lin SJ, Lai CC, Lai EC. Effect modification by indication to the risks of major thromboembolic adverse events in patients receiving intravitreal anti-vascular endothelial growth factor treatment: a population-based retrospective cohort study. BioDrugs. 2022;36(2):205-216. doi:1007/s40259-022-00516-y
  29. Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131(4):456-461. doi:1001/jamaophthalmol.2013.2379
  30. Baudin F, Benzenine E, Mariet AS, et al. Topical antibiotic prophylaxis and intravitreal injections: impact on the incidence of acute endophthalmitis-a nationwide study in France from 2009 to 2018. Pharmaceutics. 2022;14(10):2133. doi:3390/pharmaceutics14102133

Articles in Press, Corrected Proof
Available Online from 10 June 2024
  • Receive Date: 25 July 2023
  • Revise Date: 17 April 2024
  • Accept Date: 08 June 2024
  • First Publish Date: 10 June 2024