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Poorer Outcomes in Real-World Studies of Anti–Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration

      Time and time again, real-world studies have demonstrated relative undertreatment with anti–vascular endothelial growth factor (VEGF) injections and the consequent poorer outcomes compared with the landmark clinical trials, which begs the question of whether we as clinicians are doing enough to maximize visual potential for our patients. Although a treat-and-extend protocol has become the predominant algorithm used by retina specialists in the United States, evidence suggests that more frequent therapy may be needed to ensure the best outcomes.
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study.
      In this study, Kiss et al
      • Kiss S.
      • Campbell J.
      • Almony A.
      • et al.
      Management and outcomes for neovascular age-related macular degeneration: analysis of US Electronic Health Records.
      (page 1179) used the US Retina electronic health record database to analyze the functional and anatomic outcomes of a large cohort of 30 106 patients initiating anti-VEGF therapy for neovascular age-related macular degeneration (nAMD). Over the first year of treatment, eyes received an average of 6 injections and only experienced a slight +0.6 letter visual acuity improvement from baseline. Eyes receiving ≥7 injections gained approximately 2 letters compared with those receiving <7, which lost approximately 1 letter of vision from baseline. On multivariate linear regression analysis, the study found that each unit injection yielded a +0.37 letter gain. This was also one of the largest real-world studies that included anatomic changes on OCT from a subset of 3137 eyes. As expected, the mild visual acuity gain correlated with a modest decrease in mean central retinal thickness of −48 μm by month 12 compared with baseline. In contrast, clinical trial data have demonstrated 116 to 179 μm decreases in central retinal thickness. Data from another real-world study by Khanani et al
      • Khanani A.M.
      • Skelly A.
      • Bezlyak V.
      • et al.
      SIERRA-AMD: a retrospective, real-world evidence study of patients with neovascular age-related macular degeneration in the United States.
      of 79 885 patients with nAMD receiving intravitreal anti-VEGF injections found a similar mild improvement of +1.1 letters at 1 year compared with baseline despite receiving a mean of 7.5 injections, which echoes the findings in the current study. At 2 years, both studies reported a modest decrease in mean visual acuity of −1.3 letters in the report by Khanani et al
      • Khanani A.M.
      • Skelly A.
      • Bezlyak V.
      • et al.
      SIERRA-AMD: a retrospective, real-world evidence study of patients with neovascular age-related macular degeneration in the United States.
      and −1.5 letters in the study by Kiss et al
      • Kiss S.
      • Campbell J.
      • Almony A.
      • et al.
      Management and outcomes for neovascular age-related macular degeneration: analysis of US Electronic Health Records.
      compared to baseline with a mean of 6.7 and 4.9 injections in the second year, respectively. Compared with the mean gain of 6 to 11 letters seen in various clinical trials, the real-world results are clearly disappointing.
      These findings compel us to reflect on what is driving the undertreatment of patients. On one hand, treating physicians may be the root cause. Perhaps, we are sometimes too relaxed with treat-and-extend or pro re nata protocols. A combination of ever-growing clinic volumes, patient input, and concern for healthcare costs may be some of the driving factors. On the other hand, patient adherence to recommended follow-up visits may be a major underlying problem. A prior study by our group found that among 9007 patients with nAMD, 22.2% were lost to follow-up for 12 months or more immediately after an anti-VEGF injection.
      • Obeid A.
      • Gao X.
      • Ali F.S.
      • et al.
      Loss to follow-up among patients with neovascular age-related macular degeneration who received intravitreal anti–vascular endothelial growth factor injections.
      Several sociodemographic risk factors were found, including older age, lower regional-adjusted gross income, and greater distance from clinic. Older patients tend to have more medical problems and other comorbidities that may lead to breaks in treatment due to illness or hospitalizations. Most are on fixed incomes that must be used for living expenses, medications, and healthcare costs, leading them to prioritize spending based on what they can afford. Some rely on others to drive them, creating additional barriers to care, particularly if they live in locations more distant from their physicians. Ultimately, it may be unrealistic to expect real-world results to mirror clinical trials given the self-selection of motivated patients into these studies who sign a commitment, have close monitoring and reminders, often receive free transportation, and typically have no out-of-pocket costs.
      It is clear that treatment breaks have a lasting negative impact on visual outcomes in nAMD. Another study by our group found that 93 eyes of 77 patients who had a treatment break for more than 6 months after receiving an anti-VEGF injection did not return to their pre-break visual acuity after restarting therapy despite improvement in macular edema to the pre-break levels.
      • Soares R.R.
      • Mellen P.
      • Garrigan H.
      • et al.
      Outcomes of eyes lost to follow-up with neovascular age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor.
      A secondary analysis of the Comparison of AMD Treatment Trials found that patients with poorer visit adherence experienced fewer letters of vision gain compared with those who were more adherent.
      • Ramakrishnan M.S.
      • Yu Y.
      • VanderBeek B.L.
      Association of visit adherence and visual acuity in patients with neovascular age-related macular degeneration: secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial.
      Ongoing follow-up visits appear to be critical for optimizing patient outcomes. Providers may need to be more judicious about withholding or extending treatment. Interventions to improve patient compliance with follow-up recommendations will need to be further studied to see which techniques are most effective. Fortunately, hope for the future is in sight with the advent of longer-lasting pharmacologic therapies and novel delivery systems on the horizon. If proven safe and efficacious, these therapies should decrease the treatment burden for both patients and providers, and perhaps improve real-world outcomes.

      References

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        • Tadayoni R.
        • Beatty S.
        • et al.
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        Management and outcomes for neovascular age-related macular degeneration: analysis of US Electronic Health Records.
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