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Shifting Tides in Diabetic Retinopathy Treatment: The Rise of Ranibizumab and Decline of Panretinal Photocoagulation Post-Protocol S

 

  • Overview of Proliferative Diabetic Retinopathy (PDR):
    • PDR is the most advanced form of diabetic eye disease, affecting patients with type 1 and type 2 diabetes mellitus.
    • Treatment options include intravitreal anti-vascular endothelial growth factor (VEGF) therapy (e.g., ranibizumab), vitrectomy, and panretinal photocoagulation (PRP).

 

  • History of PRP:
    • Positive therapeutic effects of laser photic burns were first reported by Meyer-Schwickerath in 1954; the xenon-arc photocoagulator system was developed in 1956.
    • PRP has been a standard treatment for PDR for nearly three decades but is associated with side effects like retinal scarring, scotoma, and visual field loss.

 

  • Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S:
    • Protocol S compared PRP to ranibizumab for PDR treatment:
      • 2-year results (published November 24, 2015): Showed ranibizumab was non-inferior to PRP, with better visual outcomes and fewer complications.
      • 5-year results (published July 24, 2018): Confirmed sustained benefits of ranibizumab but noted attenuation of visual field preservation over time due to ischemic peripheral retina.

 

  • Trends in PRP and Ranibizumab Utilization:
    • Post-2015 (2-year Protocol S results):
      • Significant negative trend in PRP services (P<0.001) and positive trend in ranibizumab services (P<0.001).
      • In 2016, PRP usage decreased by 15%, while ranibizumab usage increased by 4%.
    • Post-2018 (5-year Protocol S results):
      • Continued significant negative trend in PRP services (P=0.003).
      • No significant trend in ranibizumab services (P=0.222), indicating stabilization of ranibizumab use.
    • Key Exam Point: The publication of Protocol S results is strongly associated with a shift from PRP to ranibizumab for PDR treatment.

 

  • Reimbursement Trends for PRP:
    • Significant negative trends in reimbursement factors for PRP (2013–2020, all P<0.001):
      • Average work RVU (wRVU), nonfacility physical expense RVU (PE RVU), facility PE RVU, and malpractice RVU (MP RVU).
      • Declining reimbursement may contribute to reduced PRP utilization, influenced by bundling regulations and Medicare budget cuts (e.g., 3% cut in 2013, 6% cut in 2021, 4.47% conversion factor drop in 2023).

 

  • Reasons for Increased Ranibizumab Use:
    • More robust treatment effect in PDR with diabetic macular edema (DME).
    • Lower incidence of complications (e.g., vitreous hemorrhage, retinal detachment, neovascular glaucoma) compared to PRP.
    • Improved cost-effectiveness in patients with PDR and DME.
    • Financial rebates for anti-VEGF therapy may incentivize ranibizumab use.
    • Key Exam Point: Ranibizumab treats both PDR and DME, unlike PRP, which has limited utility in reversing neovascularization.

 

  • Reasons for Decreased PRP Use:
    • Side effects: retinal destruction, scotoma, visual field loss, decreased night/color vision, contrast sensitivity, worsening DME, pupil dilation.
    • Inability to reverse neovascularization (unlike anti-VEGF, which induces regression).
    • Limited efficacy in certain populations (e.g., severe PDR with tractional components or late-stage disease).
    • CLARITY Study (published May 7, 2017): Demonstrated aflibercept was non-inferior and superior to PRP for PDR, further supporting anti-VEGF preference.
    • Key Exam Point: Anti-VEGF therapies (ranibizumab, aflibercept) are preferred over PRP due to better efficacy and fewer side effects in many cases.

 

  • Real-Life Challenges with Ranibizumab:
    • High loss to follow-up rate (>50%) in PDR patients, a chronic disease requiring long-term monitoring.
    • PRP offers a more permanent effect, making it preferable for patients with inconsistent follow-up.
    • Despite these challenges, ranibizumab utilization continues to rise.
  • Study Limitations:
    • Data limited to Medicare-reimbursed ophthalmologists.
    • Did not examine other anti-VEGF agents (e.g., bevacizumab, aflibercept).
    • Dataset does not separate PRP/ranibizumab use by diagnosis (e.g., includes non-PDR indications like age-related macular degeneration or retinal vein occlusion).
    • Findings are associative, not causal.

 

  • Conclusion:
    • Protocol S significantly influenced treatment patterns, with increased ranibizumab and decreased PRP use starting in 2016.
    • PRP remains relevant for patients with severe PDR or unreliable follow-up due to its durability and cost-effectiveness, despite declining reimbursement.

Citation

Shah S, Chou B, Patel M, Watane A, Shah L, Yannuzzi N, Sridhar J. Review and analysis of history and utilization of panretinal photocoagulation and ranibizumab after publication of protocol S. Curr Opin Ophthalmol. 2024;35(5):369-375. doi:10.1097/ICU.0000000000001076