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Management and Outcomes for Neovascular Age-Related Macular Degeneration

Analysis of United States Electronic Health Records
Open AccessPublished:February 27, 2020DOI:https://doi.org/10.1016/j.ophtha.2020.02.027

      Purpose

      To assess anti-vascular endothelial growth factor (VEGF) management patterns and anatomic and visual acuity (VA) outcomes among patients with neovascular age-related macular degeneration (nAMD) in United States clinical practice.

      Design

      Retrospective observational cohort study.

      Participants

      Patients (N = 30 106) initiating intravitreal anti-VEGF treatment for nAMD between October 2009 and November 2016.

      Methods

      Analysis of longitudinal electronic health records from USRetina.

      Main Outcome Measures

      Number of intravitreal injections, OCT examinations, and fluorescein angiography (FA) examinations per study eye during the first 12 months; corrected VA and central retinal thickness (CRT) at 12 months; and number of ophthalmologist visits, stratified by index anti-VEGF agent.

      Results

      Over the first 12 months, patients made a mean of 8.1 (range, 1–39) ophthalmologist visits, received a mean of 6.0 (range, 1–27) anti-VEGF injections, and underwent 7.2 OCT and 5.3 FA examinations per study eye. For eyes with paired baseline and 12-month readings, mean CRT declined from 320 to 271 μm (mean change, –48 μm), and mean VA increased from 60.3 to 61.0 approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letters (mean change, +0.6 letters). Twelve months after initiating index treatment with bevacizumab, ranibizumab, and aflibercept, 19.3%, 15.8%, and 15.5% of eyes, respectively, showed greater than 10-letter gain, whereas 13.2%, 14.7%, and 14.4% of eyes, respectively, showed greater than 10-letter loss. Mean change from baseline VA at 12 months increased linearly with cumulative anti-VEGF injection count: +1.79 versus –0.95 approximate ETDRS letters for eyes receiving 7 or more injections versus fewer than 7 injections. Similarly, the magnitude of the reduction from baseline CRT at 12 months tended to increase linearly with increasing number of anti-VEGF injections. Multivariate linear regression analysis, adjusted for covariates, indicated a significant association between cumulative number of anti-VEGF injections and change from baseline in VA at 12 months, with each unit increase producing an estimated gain of 0.37 approximate ETDRS letters.

      Conclusions

      This analysis of combined morphologic and functional outcomes of anti-VEGF therapy, the largest conducted to date in nAMD, identified relatively low anti-VEGF injection frequencies, coupled with moderate anatomic and limited VA improvements, in United States clinical practice.

      Abbreviations and Acronyms:

      ANCHOR (Anti-Vascular Endothelial Growth Factor Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-related Macular Degeneration), CATT (Comparison of Age-Related Macular Degeneration Treatments Trials), CRT (central retinal thickness), EHR (electronic health record), ETDRS (Early Treatment Diabetic Retinopathy Study), FA (fluorescein angiography), HARBOR (Phase III Double-Masked, Multicenter, Randomized, Active Treatment-Controlled Study of the Efficacy and Safety of 0.5 mg and 2.0 mg Ranibizumab Administered on a Monthly or As-Needed Basis in Patients with Subfoveal Neovascular Age-Related Macular Degeneration), ICD-9-CM (International Classification of Diseases, 9th edition, Clinical Modification), IRIS (Intelligent Research in Sight), nAMD (neovascular age-related macular degeneration), PRN (pro re nata), SD (standard deviation), SUSTAIN (Safety and Efficacy of a Flexible Dosing Regimen of Ranibizumab in Neovascular Age-related Macular Degeneration), TREND (Treat-and-Extend Versus Monthly Regimen in Neovascular Age-Related Macular Degeneration), TREX-AMD (Treat and Extend Protocol in Patients with Wet Age-related Macular Degeneration), VA (visual acuity), VEGF (vascular endothelial growth factor), VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD)
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      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
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      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
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      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
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      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
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      Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials.
      ,
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      • Ritter M.
      • Bolz M.
      • et al.
      Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related macular degeneration.
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      Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related macular degeneration.
      A recent analysis of 15 nAMD trials using various dosing regimens of intravitreal bevacizumab 1.25 mg, ranibizumab 0.5 mg, and aflibercept 0.5 or 2 mg, including monthly,
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
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      Ranibizumab for neovascular age-related macular degeneration.
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      CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      ,
      • Heier J.S.
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      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
      ,
      • Wykoff C.C.
      • Croft D.E.
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      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
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      • Kaiser P.K.
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      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
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      Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      quarterly,
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      • Guymer R.
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      Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study.
      ,
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      • Yue H.
      • Wilson L.
      Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2.
      pro re nata (PRN),
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      CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      ,
      • Boyer D.S.
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      • Brown D.M.
      • et al.
      A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration.
      ,
      • Holz F.G.
      • Amoaku W.
      • Donate J.
      • et al.
      Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study.
      ,
      • Chakravarthy U.
      • Harding S.P.
      • Rogers C.A.
      • et al.
      Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.
      ,
      • Ho A.C.
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      and treat-and-extend
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      dosing, reported a modest linear correlation between mean injection frequency (range, 4.6–13 injections) and mean ETDRS letter gain at 12 months, with a ceiling effect of diminishing additional visual benefit being evident with 9 or more injections.
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      Intensive intravitreal dosing regimens place a burden on patients and healthcare services, and implementation of regular monthly monitoring and dosing in routine clinical practice poses a challenge. Prompted by the desire to reduce treatment demands, anti-VEGF treatment approaches have evolved from fixed monthly dosing to discontinuous PRN and treat-and-extend regimens.
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      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      ,
      • Fung A.E.
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      • Rosenfeld P.J.
      • et al.
      An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
      or a treat-and-extend injection regimen with highly individualized dosing
      • Wykoff C.C.
      • Croft D.E.
      • Brown D.M.
      • et al.
      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
      ,
      • Oubraham H.
      • Cohen S.Y.
      • Samimi S.
      • et al.
      Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration.
      ,
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      ,
      • Silva R.
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      • Larsen M.
      • et al.
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      can achieve VA gains approaching those obtained with fixed monthly dosing. However, real-world observational studies, conducted predominantly in Europe in the early years (approximately 2006–2012) after ranibizumab’s introduction, have indicated generally low injection and monitoring frequencies in routine clinical practice and inferior VA gains compared with those achieved with fixed frequent dosing or PRN administration in pivotal clinical trials.
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      ,
      • Kim L.N.
      • Mehta H.
      • Barthelmes D.
      • et al.
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      Real-world anti-VEGF treatment patterns in nAMD vary from country to country,
      • Holz F.G.
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      • Beatty S.
      • et al.
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      reflecting the varying parameters under which different healthcare systems, treating physicians, and patients operate. Information on anti-VEGF use patterns and VA outcomes among patients with nAMD in the United States comes largely from 2 large retrospective claims analyses based on Truven Health Analytics’ MarketScan Research and IMS Health’s LifeLink Health Plan data for 2005 through 2011,
      • Holekamp N.M.
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      • Yeh W.S.
      • et al.
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      ,
      • Kiss S.
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      • et al.
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      a retrospective study of electronic medical records for 2011 through 2015,
      • Lotery A.
      • Griner R.
      • Ferreira A.
      • et al.
      Real-world visual acuity outcomes between ranibizumab and aflibercept in treatment of neovascular AMD in a large US data set.
      and a retrospective analysis of Intelligent Research in Sight (IRIS) registry data for 2013 through 2016.
      • Rao P.
      • Lum F.
      • Wood K.
      • et al.
      Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry.
      Notably, these studies did not assess the level of anatomic control achieved with anti-VEGF therapy in the real-world setting. The present study provides an up-to-date assessment of real-world anti-VEGF treatment patterns as well as both anatomic and VA outcomes in nAMD based on electronic health records (EHRs) from USRetina.

      Methods

       Study Design and Data Source

      This retrospective observational cohort study was based on longitudinal EHRs covering the period 2008 to 2017 sourced from USRetina, one of the largest associations of private retina practices in the United States, representing 265 practices and more than 1100 physicians (https://www.usretina.com/). USRetina practices are distributed widely nationwide, with most practices located in the eastern geographic regions of the United States. The USRetina data repository includes the records of approximately 800 000 publicly insured (including Medicare and Medicaid) and privately insured patients from 2009 to the present and predominantly comprises clinical data, with additional administrative claims and financial information. The clinical content includes demographics, medical histories, clinical laboratory and examination findings, diagnoses, medications and procedures, and patient outcomes. All patient data used in this study were de-identified in compliance with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act of 1996. Institutional review board or ethics committee approval was not required for this study.

       Patient Identification

      The USRetina database was screened to identify patients who (1) had received an intravitreal injection of ranibizumab, bevacizumab, or aflibercept (Healthcare Common Procedure Coding System codes J9035, J3490, Q2024, J3590, C9257, Q9977, J7999, J2778, and J0178) between October 1, 2009, and November 1, 2016 (index period), with no anti-VEGF injection during the 12 months preceding the initial (index) injection; (2) had a diagnosis of nAMD (International Classification of Diseases, 9th edition, Clinical Modification [ICD-9-CM] codes 362.42, 362.43, 362.50, and 362.52) in the treated (study) eye before or on the day of the index injection; and (3) had 12 or more months of continuous enrollment both before and after the index injection. For patients undergoing treatment with multiple anti-VEGF agents (bevacizumab, ranibizumab, or aflibercept), the agent administered in the initial injection was designated the index anti-VEGF agent. Patients with a codiagnosis of other retinal disease, namely diabetic retinopathy (ICD-9-CM codes 362.01–362.06), diabetic macular edema (ICD-9-CM code 362.07), uveitis (ICD-9-CM codes 360.11, 360.12, 363.0x, 363.10, 363.11, 363.12, 363.13, 363.14, 363.15, 363.20, 363.01, 363.02, and 364.xx), retinal vein occlusion (ICD-9-CM codes 362.35 and 362.36), and dry age-related macular degeneration (ICD-9-CM codes 362.51 and 362.57) in the study eye were excluded from study participation, as were patients for whom the laterality of retinal disease or the index injection could not be established. If both eyes satisfied the study eligibility criteria, both eyes were included in the analysis.

       Study Outcomes

      Patient management patterns over the 12-month period after the index intravitreal injection were assessed in terms of the numbers of anti-VEGF injections, OCT examinations (Current Procedural Terminology codes 92132, 92133, and 92134), and fluorescein angiography (FA) examinations (Current Procedural Terminology code 92235) undergone per study eye and the number of ophthalmology clinic visits made per patient. Corrected VA values, which were measured in clinical practice using Snellen charts, were converted to approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores using a published algorithm.
      • Gregori N.Z.
      • Feuer W.
      • Rosenfeld P.J.
      Novel method for analyzing Snellen visual acuity measurements.
      Central retinal thickness (CRT) measurements were obtained in clinical practice using spectral-domain OCT (predominantly) or time-domain OCT. Vision and anatomic outcomes at the 3-month (days 60–149), 6-month (days 150–239), 9-month (days 240–329), and 12-month (days 330–419) clinic visits were expressed as the change in approximate ETDRS letter score and CRT value from the baseline visit (days –30 to 7) and the proportions of study eyes with 10-letter approximate ETDRS or more gain or loss. For the primary analysis of visual and anatomic outcomes, study eyes were stratified according to index anti-VEGF agent. Visual acuity outcomes (absolute value and change from baseline at 12 months) were additionally stratified according to baseline VA value. Secondary analyses were conducted to explore the relationship between anti-VEGF injection frequency over the first 12 months and (1) change from baseline in VA at 12 months and (2) change from baseline in CRT at 12 months. Analyses were based on observed VA and CRT readings, with no imputation of values for missing time points.

       Statistical Analysis

      Data were summarized with descriptive statistics. Multivariate linear regression models were used to explore the effects of covariates (age, gender, baseline VA, baseline CRT, index anti-VEGF agent, cumulative number of anti-VEGF injections, and presence of intraretinal or subretinal fluid) on VA response (change in VA from baseline) at 12 months. Allowance was made for data correlation resulting from inclusion of paired study eyes by adjusting for clustered standard errors. Statistical significance was set at P < 0.05.

      Results

       Study Population

      Of the 71 370 patients (90 856 eyes) identified in the USRetina database as having received an anti-VEGF injection between October 1, 2009, and November 1, 2016 (index period), 30 106 patients (37 021 eyes) met the full eligibility criteria and were included in the analysis (Fig 1). Of these, 23 191 patients (77.0%) provided a single study eye and 6915 patients (23.0%) provided paired study eyes for the analysis. The study population was predominantly white (90.1%) and female (62.8%), with a mean age of 80.5 years (standard deviation [SD], 9.5 years; Table 1). At the time of the index intravitreal injection (baseline), mean VA (based on data for 23 816 eyes) was 58.1 approximate ETDRS letters (SD, 18.9 approximate ETDRS letters; Snellen equivalent, approximately 20/70) and mean CRT (based on data from 5185 eyes) was 320 μm (SD, 119 μm). Corresponding median VA and CRT values were 61 approximate ETDRS letters (Snellen equivalent, approximately 20/60) and 294 μm, respectively.
      Figure thumbnail gr1
      Figure 1Flowchart showing patient selection algorithm. AMD = age-related macular degeneration; VEGF = vascular endothelial growth factor.
      Table 1Baseline Demographics and Clinical Characteristics
      CharacteristicData
      Patient level (n = 30 106)
       Mean age (SD), yrs80.5 (9.5)
       Female gender, no. (%)18 895 (62.8)
       Ethnicity, n (%)
      White27 137 (90.1)
      Black497 (1.7)
      Asian278 (0.9)
      Other39 (0.1)
      Unspecified/unknown2155 (7.2)
       Region, no. (%)
      South15 005 (49.8)
      Midwest6829 (22.7)
      Northeast8210 (27.3)
      West55 (0.2)
      Unspecified/unknown7 (0.02)
       Insurance type
      Public16 984 (56.4)
      Private13 086 (43.5)
      Uninsured36 (0.1)
       Concomitant ocular disease in contralateral (nonstudy) eye, no. (%)
      Dry AMD16 885 (56.1)
      Cataract9039 (30.0)
      Diabetic retinopathy902 (3.0)
       Eye level (n = 37 021)
       Baseline corrected visual acuity (Snellen), no. (%)
      20/40 or better8855 (23.9)
      20/50–20/808261 (22.3)
      20/90–20/1601941 (5.2)
      20/200 or worse4759 (12.9)
      Unknown13 205 (35.7)
      AMD = age-related macular degeneration; SD = standard deviation.

       Treatment and Monitoring Pattern over the First 12 Months

      Intravitreal anti-VEGF therapy was initiated with bevacizumab in 14 927 eyes (40.3%), ranibizumab in 13 999 eyes (37.8%), and aflibercept in 8095 eyes (21.9%), and patients were followed up for a median of 109 weeks (25th–75th percentiles, 65.3–152.0 weeks). Over the first 12 months of treatment, eyes received a mean of 6.0 anti-VEGF injections (SD, 3.1 injections; range, 1–27 injections). Corresponding mean values for the individual agents were as follows: bevacizumab, 5.8 injections (SD, 3.3 injections; range, 1–23 injections); ranibizumab, 6.1 injections (SD, 3.0 injections; range, 1–27 injections); and aflibercept, 6.1 injections (SD, 3.0 injections; range, 1–20 injections). Over the course of follow-up (median, 109 weeks), 10 131 eyes (27.4%) were switched to another anti-VEGF agent. For those eyes that were captured switching during follow-up (the duration of which varied from eye to eye), the mean time to first switch was 42 weeks, and the mean injection number at first switch was 7.
      For the patients who received an index intravitreal anti-VEGF injection (n = 30 106), the mean number of ophthalmology clinic visits during the first 12 months of treatment was 8.1 (SD, 4.6 visits; range, 1–39 visits). In total, 36 721 eyes (99.2%) underwent OCT, with a mean of 7.2 OCT examinations per eye (SD, 3.3 examinations), and 16 597 eyes (44.8%) underwent FA, with a mean of 5.3 FA examinations per eye (SD, 4.2 examinations) over the first 12 months of treatment. Corresponding 12-month results for eyes that were initiated on treatment with the individual agents were bevacizumab, mean 7.0 OCT examinations (SD, 3.4 examinations) and 4.2 FA examinations (SD, 4.0 examinations); ranibizumab, mean 7.4 OCT examinations (SD, 3.2 examinations) and 6.8 FA examinations (SD, 3.9 examinations); and aflibercept, mean 7.4 OCT examinations (SD, 3.2 examinations) and 5.8 FA examinations (SD, 4.1 examinations). The frequency of FA use increased from 2012 through 2015, subsequently stabilizing at a plateau of approximately 5.5 to 6.0 examinations per eye over the first 12 months of treatment for eyes initiating treatment in 2016.

       Anatomic and Visual Acuity Outcomes over the First 12 Months

      Among eyes with anatomic readings both at baseline and 12 months post-index (n = 3137), mean CRT declined from 319.7 to 271.3 μm over this period, representing a mean change of –48.4 μm (SD, 134.0 μm; median change, –24 μm). Corresponding (baseline vs. 12-month) CRT values for the individual anti-VEGF agents were: bevacizumab (n = 2361), mean 330.5 μm versus 276.0 μm (mean change, –54.5 μm; median change, –27 μm); ranibizumab (n = 384), mean 278.6 μm versus 249.1 μm (mean change, –29.5 μm; median change, –18 μm); and aflibercept (n = 392), mean 294.8 μm versus 264.6 μm (mean change, –30.2 μm; median change, –16 μm). Profiles of mean CRT over the 12-month post-index period, stratified by index anti-VEGF agent, are shown in Figure 2A.
      Figure thumbnail gr2
      Figure 2Graphs showing (A) anatomic and (B) visual outcomes stratified by index anti-vascular endothelial growth factor agent. ETDRS = Early Treatment Diabetic Retinopathy Study.
      Among eyes with VA readings at both baseline and 12 months (n = 16 445), mean VA increased from 60.3 approximate ETDRS letters (Snellen equivalent, approximately 20/63) at baseline to 61.0 approximate ETDRS letters (Snellen equivalent, approximately 20/60) at 12 months, representing a mean change of +0.6 approximate ETDRS letters (SD, 14.0 letters) over this period. Corresponding (baseline vs. 12-month) VA values for the individual anti-VEGF agents were: bevacizumab (n = 5779), mean 59.7 approximate ETDRS letters versus 61.2 approximate ETDRS letters (mean change, +1.6 approximate ETDRS letters); ranibizumab (n = 6612), mean 60.6 approximate ETDRS letters versus 60.7 approximate ETDRS letters (mean change, +0.1 approximate ETDRS letters); and aflibercept (n = 4054), mean 61.0 approximate ETDRS letters versus 61.0 approximate ETDRS letters (mean change, +0.0 approximate ETDRS letters). Profiles of mean VA over 12 months post-index, stratified by index anti-VEGF agent, are shown in Figure 2B. Eyes with worse visual impairment at baseline showed the greatest improvements in VA over the first 12 months but failed to achieve the absolute VA levels of eyes with milder visual impairment at baseline (Fig 3). At 12 months after initiation of index treatment with bevacizumab, ranibizumab, and aflibercept, 19.3% (1114/5779), 15.8% (1044/6612), and 15.5% (627/4054) of eyes, respectively, recorded greater than 10-letter gain in VA from baseline (9.8% [564/5779], 7.4% [492/6612], and 7.8% [316/4054] of eyes achieved a ≥15-letter gain), whereas 13.2% (761/5779), 14.7% (970/6612), and 14.4% (585/4054) of eyes, respectively, showed greater than 10-letter loss.
      Figure thumbnail gr3
      Figure 3Graphs showing visual acuity outcomes stratified by baseline visual acuity: (A) corrected visual acuity change from baseline and (B) corrected visual acuity. ETDRS = Early Treatment Diabetic Retinopathy Study.
      Among the subset of eyes that had paired VA readings at baseline and 12 months, and additionally showed a baseline VA of 20/40 or better (n = 6776), a mean decline in VA of –2.8 approximate ETDRS letters (SD, 9.3 letters) was recorded over the 12-month treatment period. Corresponding VA changes over this period for the individual anti-VEGF agents were: bevacizumab (n = 2299), mean –2.5 approximate ETDRS letters; ranibizumab (n = 2747), mean –2.9 approximate ETDRS letters; and aflibercept (n = 1730), mean 0.0 approximate ETDRS letters. At 12 months, three quarters of bevacizumab-, ranibizumab-, and aflibercept-treated eyes (78.7%, 76.0%, and 77.2%, respectively) retained a VA of 20/40 or better.
      A separate analysis of vision outcomes, focusing specifically on the subset of 3137 eyes (<10% of the overall study population) that provided OCT data for assessment of anatomic outcomes, demonstrated a mean change (from baseline) in corrected VA of +1.9 approximate ETDRS letters at 12 months (based on 1555 eyes within this subset with paired VA readings at baseline and 12 months post-index).

       Treatment Patterns and Visual Acuity Outcomes over the Second 12 Months

      Overall, the mean number of intravitreal anti-VEGF injections administered during the second 12 months of treatment was 4.9 (SD, 2.8). For the cohort of eyes with VA readings at both baseline and 24 months (n = 10 663), mean VA at 24 months was 60.1 approximate ETDRS letters (Snellen equivalent, approximately 20/63) and the mean change from baseline was –1.5 approximate ETDRS letters (SD, 15.3 letters). Findings at 24 months, stratified by baseline VA, were similar to those at 12 months, with the greatest vision gain achieved in eyes with the worst VA at baseline. Additional second-year analysis findings are provided in the Supplemental Materials (available at www.aaojournal.org).

       Association between Injection Frequency and Clinical Outcomes

      For the subgroup of eyes providing VA data at both baseline and 12 months post-index (n = 16 445), mean change from baseline VA at 12 months tended to increase linearly with an increasing number of anti-VEGF injections received in the first 12 months of treatment (Fig 4). The mean change from baseline VA at 12 months was greater in eyes receiving 7 or more injections over this period (n = 9365) than in eyes receiving fewer than 7 injections (n = 7080; +1.79 approximate ETDRS letters vs. –0.95 approximate ETDRS letters). Similarly, for those eyes with anatomic data at baseline and 12 months post-index (n = 3137), the magnitude of the reduction from baseline in CRT at 12 months tended to increase linearly with an increasing number of anti-VEGF injections received over this period (Fig 5).
      Figure thumbnail gr4
      Figure 4Graph showing the association between number of anti-vascular endothelial growth factor injections and visual acuity outcome at 12 months. CVA = corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study.
      Figure thumbnail gr5
      Figure 5Graph showing the association between number of anti-vascular endothelial growth factor injections and central retinal thickness (CRT) outcome at 12 months.
      Multivariate linear regression analysis with adjustment for potential confounders of age, gender, baseline VA, and index anti-VEGF agent revealed a significant association between the cumulative number of injections received at 12 months and the change from baseline in VA at 12 months (β coefficient, 0.37; P = 0.01; Table 2). Thus, each unit increase in the number of anti-VEGF injections resulted in an estimated gain of 0.37 approximate ETDRS letters. Of the covariates, age and baseline VA also demonstrated significant (P < 0.05) associations with change from baseline VA at 12 months. However, the regression model accounted for only 14% of the observed variation in change in VA at 12 months. A rerun of the model, with cumulative number of anti-VEGF injections expressed as a categorical variable, indicated that eyes receiving 1 to 9 injections and eyes receiving 11 or more injections tended to achieve smaller and greater VA improvements, respectively, at 12 months than eyes receiving 10 injections (reference value).
      Table 2Multivariate Linear Regression Analysis of Change from Baseline in Corrected Visual Acuity at 12 Months
      CovariateCoefficient EstimateStandard ErrorP Value
      Intercept30.7600.0320.0007
      Left eye–0.1610.0020.009
      Age–0.1910.0050.016
      Male gender0.0260.1290.874
      Baseline corrected visual acuity–0.2820.0040.009
      Index anti-VEGF agent
       Aflibercept–0.8780.0950.069
       Ranibizumab–0.7400.4600.354
      Cumulative no. of injections at 12 months0.3710.0060.010
      VEGF = vascular endothelial growth factor.
      Coefficient estimates for aflibercept and ranibizumab are expressed using bevacizumab as the reference index anti-VEGF agent.

      Discussion

      This retrospective analysis of EHRs of more than 30 000 patients initiating anti-VEGF (bevacizumab, ranibizumab, or aflibercept) therapy for nAMD in the United States between 2009 and 2016 indicated that treatment and monitoring frequencies over the first 12 months fell short of the more frequent schedules used in landmark randomized clinical trials of monthly, treat-and-extend, and PRN regimens, such as ANCHOR, HARBOR, VIEW, TREX-AMD, CATT, and Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration (TREND),
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      ,
      • Martin D.F.
      • Maguire M.G.
      • et al.
      CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      ,
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
      • Wykoff C.C.
      • Croft D.E.
      • Brown D.M.
      • et al.
      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
      ,
      • Silva R.
      • Berta A.
      • Larsen M.
      • et al.
      Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: results with ranibizumab from the TREND study.
      and the functional outcome in particular was inferior to that reported in these trials. On average, during the first 12 months of treatment, patients attended 8.1 ophthalmology clinic visits, received 6.0 intravitreal anti-VEGF injections, and underwent 7.2 OCT and 5.3 FA examinations per eye. Only 19% of eyes received treatment at a rate approximating monthly dosing (i.e., 10 or more injections over the first 12 months). Overall, treatment and disease monitoring patterns were similar among the individual agents. Functional improvements were modest, with VA increasing from a mean of 60.3 approximate ETDRS letters (Snellen equivalent, approximately 20/63) to 61.0 approximate ETDRS letters (Snellen equivalent, approximately, 20/60) at 12 months, representing an average gain of 0.6 approximate ETDRS letters, and less than 20% of eyes achieved greater than 10-letter gain. In contrast, the HARBOR, VIEW, TREX-AMD, CATT, and TREND studies, which enrolled eyes with a comparable level of vision impairment (mean baseline BCVA, 52‒61 ETDRS letters; Snellen equivalent, approximately 20/100‒20/60) to that of our sample, reported mean VA gains of 5.9 to 11.1 ETDRS letters at 12 months.
      • Martin D.F.
      • Maguire M.G.
      • et al.
      CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      ,
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
      • Wykoff C.C.
      • Croft D.E.
      • Brown D.M.
      • et al.
      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
      ,
      • Silva R.
      • Berta A.
      • Larsen M.
      • et al.
      Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: results with ranibizumab from the TREND study.
      Anatomic improvement amounted to a mean reduction in CRT of 48 μm after 12 months of treatment from a baseline of 320 μm. For comparison, corresponding CRT reductions in the HARBOR and VIEW studies, which included eyes with a similar degree of retinal thickening (mean baseline CRT, 313‒348 μm) to that in our sample, ranged from 116 to 172 μm.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      ,
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
      Our findings are in accordance with those of previous real-world studies of anti-VEGF (predominantly ranibizumab) use and outcomes in nAMD, which have indicated generally low numbers of injections (approximately 4–6)
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration.
      ,
      • Finger R.P.
      • Wiedemann P.
      • Blumhagen F.
      • et al.
      Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.
      • Holz F.G.
      • Bandello F.
      • Gillies M.
      • et al.
      Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme.
      • Rakic J.M.
      • Leys A.
      • Brié H.
      • et al.
      Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study.
      • Cohen S.Y.
      • Mimoun G.
      • Oubraham H.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
      • Souied E.H.
      • Oubraham H.
      • Mimoun G.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the TWIN study.
      Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group
      The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity.
      • Eldem B.
      • Lai T.Y.Y.
      • Ngah N.F.
      • et al.
      An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.
      • Kataja M.
      • Hujanen P.
      • Huhtala H.
      • et al.
      Outcome of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration in real-life setting.
      • Chavan R.
      • Panneerselvam S.
      • Adhana P.
      • et al.
      Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.
      • Gabai A.
      • Veritti D.
      • Lanzetta P.
      One-year outcome of ranibizumab for neovascular age-related macular degeneration: a thorough analysis in a real-world clinical setting.
      and ophthalmology visits (approximately 7–9)
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration.
      ,
      • Rakic J.M.
      • Leys A.
      • Brié H.
      • et al.
      Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study.
      • Cohen S.Y.
      • Mimoun G.
      • Oubraham H.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
      • Souied E.H.
      • Oubraham H.
      • Mimoun G.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the TWIN study.
      Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group
      The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity.
      • Eldem B.
      • Lai T.Y.Y.
      • Ngah N.F.
      • et al.
      An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.
      ,
      • Chavan R.
      • Panneerselvam S.
      • Adhana P.
      • et al.
      Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.
      ,
      • Gabai A.
      • Veritti D.
      • Lanzetta P.
      One-year outcome of ranibizumab for neovascular age-related macular degeneration: a thorough analysis in a real-world clinical setting.
      and limited VA improvements (–1 to +4 letters)
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration.
      ,
      • Finger R.P.
      • Wiedemann P.
      • Blumhagen F.
      • et al.
      Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.
      • Holz F.G.
      • Bandello F.
      • Gillies M.
      • et al.
      Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme.
      • Rakic J.M.
      • Leys A.
      • Brié H.
      • et al.
      Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study.
      • Cohen S.Y.
      • Mimoun G.
      • Oubraham H.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
      • Souied E.H.
      • Oubraham H.
      • Mimoun G.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the TWIN study.
      Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group
      The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity.
      • Eldem B.
      • Lai T.Y.Y.
      • Ngah N.F.
      • et al.
      An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.
      • Kataja M.
      • Hujanen P.
      • Huhtala H.
      • et al.
      Outcome of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration in real-life setting.
      • Chavan R.
      • Panneerselvam S.
      • Adhana P.
      • et al.
      Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.
      • Gabai A.
      • Veritti D.
      • Lanzetta P.
      One-year outcome of ranibizumab for neovascular age-related macular degeneration: a thorough analysis in a real-world clinical setting.
      • Matsumiya W.
      • Honda S.
      • Kusuhara S.
      • et al.
      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.
      • Muether P.S.
      • Hoerster R.
      • Hermann M.M.
      • et al.
      Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration.
      and CRT reductions (≤100 μm)
      • Finger R.P.
      • Wiedemann P.
      • Blumhagen F.
      • et al.
      Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.
      ,
      • Chavan R.
      • Panneerselvam S.
      • Adhana P.
      • et al.
      Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.
      • Gabai A.
      • Veritti D.
      • Lanzetta P.
      One-year outcome of ranibizumab for neovascular age-related macular degeneration: a thorough analysis in a real-world clinical setting.
      • Matsumiya W.
      • Honda S.
      • Kusuhara S.
      • et al.
      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.
      • Muether P.S.
      • Hoerster R.
      • Hermann M.M.
      • et al.
      Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration.
      after 12 months of treatment. In the largest of the European studies, a retrospective analysis (2006–2012) of EHRs of 11 135 United Kingdom patients of similar age (mean, 79.7 years) and baseline corrected VA (55 approximate ETDRS letters; Snellen equivalent, approximately 20/80) to those in our study, mean numbers of ranibizumab injections and ophthalmology visits in the first 12 months were 5.7 and 9.2, respectively, whereas mean VA improvement at 12 months was 2 letters.
      Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group
      The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity.
      Likewise, in the United States, 2 retrospective analyses based on Truven Health Analytics’ MarketScan Research and IMS Health’s LifeLink Health Plan administrative claims data (2005–2011) for patients receiving anti-VEGF therapy for nAMD (n = 19 026 and n = 11 688, respectively) indicated low uptake of ophthalmology visits (mean, 6.8–8.8), bevacizumab injections (mean, 4.5–5.5), ranibizumab injections (mean, 6.0–6.9), OCT scans (mean, 4.8–7.1), and FA examinations (mean, 1.6–2.3) during the first year of treatment.
      • Holekamp N.M.
      • Liu Y.
      • Yeh W.S.
      • et al.
      Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.
      ,
      • Kiss S.
      • Liu Y.
      • Brown J.
      • et al.
      Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.
      A more recent retrospective analysis of the IRIS registry data (2013–2016) for patients receiving bevacizumab, ranibizumab, and aflibercept monotherapy for nAMD (n = 13 859) reported injection frequencies of 5.9, 6.4, and 6.2, respectively, during the first 12 months and a 15-letter or more gain in VA in 22.7%, 20.1%, and 17.8% of patients, respectively, at 12 months.
      • Rao P.
      • Lum F.
      • Wood K.
      • et al.
      Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry.
      These favorable rates of 3-line vision gain (approximately 2-fold higher than those obtained in the USRetina dataset) may be due in part to possible selection bias in favor of so-called good responders, because the IRIS data excluded patients undergoing treatment switch. Information on real-world anatomic outcomes with anti-VEGF therapy (ranibizumab) in nAMD is more limited and derived from smaller-scale studies (typically fewer than 100 patients); these studies are nevertheless generally consistent in their findings of moderate (approximately 20%–25%) reductions in CRT after 12 months of treatment.
      • Finger R.P.
      • Wiedemann P.
      • Blumhagen F.
      • et al.
      Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.
      ,
      • Chavan R.
      • Panneerselvam S.
      • Adhana P.
      • et al.
      Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.
      ,
      • Matsumiya W.
      • Honda S.
      • Kusuhara S.
      • et al.
      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.
      ,
      • Muether P.S.
      • Hoerster R.
      • Hermann M.M.
      • et al.
      Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration.
      The largest of these studies (Lucentis in Wet AMD: Evaluation of Visual Acuity and Quality of Life; WAVE), which provided prospective OCT data from patients receiving ranibizumab in routine clinical practice in Germany (n = 871), reported mean CRT reductions of 79 and 99 μm at 3 and 12 months, respectively, from a 349-μm baseline.
      • Finger R.P.
      • Wiedemann P.
      • Blumhagen F.
      • et al.
      Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.
      One unexpected finding of the present analysis was the high frequency of FA examinations during the first year of treatment (mean, 5.3 examinations per study eye undergoing FA), which differs from findings of other real-world investigations of disease management patterns in nAMD.
      • Holekamp N.M.
      • Liu Y.
      • Yeh W.S.
      • et al.
      Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.
      ,
      • Kiss S.
      • Liu Y.
      • Brown J.
      • et al.
      Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.
      A retrospective analysis of administrative claims data from Truven Health Analytics’ MarketScan Research database reported a mean of 2.1 and 2.2 FA examinations over the first 12 months of treatment among patients initiating bevacizumab and ranibizumab, respectively, between 2008 and 2010 for newly diagnosed nAMD.
      • Holekamp N.M.
      • Liu Y.
      • Yeh W.S.
      • et al.
      Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.
      Similarly, an analysis of IMS Health’s LifeLink Health Plan database reported a mean of 1.8 and 1.7 FA examinations during the first treatment year in nAMD patients initiating bevacizumab and ranibizumab therapy, respectively, between 2008 and 2010.
      • Kiss S.
      • Liu Y.
      • Brown J.
      • et al.
      Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.
      However, these earlier reports of FA use were calculated on a per-patient rather than per-user basis. Expressed in these terms, FA use in the USRetina dataset (which was confined to 45% of the study population) equates to a mean of 2.4 procedures per patient overall, a figure broadly consistent with previously reported values.
      • Holekamp N.M.
      • Liu Y.
      • Yeh W.S.
      • et al.
      Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.
      ,
      • Kiss S.
      • Liu Y.
      • Brown J.
      • et al.
      Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.
      Confirmatory checks performed on the USRetina dataset indicated consistency between the EHR data and billing data for FA examinations and excluded the possibility of duplication of FA counts (e.g., in the case of patients undergoing bilateral treatment) or miscoding errors in the data capture process. It is perhaps pertinent that the practices contributing patients to the USRetina database were exclusively retina specialists: FA use in this subspecialty group may be anticipated to be higher than in the broader spectrum of ophthalmology practices included in the MarketScan and LifeLink datasets. Further assessment of the role of FA in the management of nAMD in clinical practice would be instructive. Although fundus FA is routinely incorporated into the protocols of prospective clinical trials of anti-VEGF therapy in nAMD,
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      ,
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      Ranibizumab for neovascular age-related macular degeneration.
      ,
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      ,
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
      ,
      • Holz F.G.
      • Amoaku W.
      • Donate J.
      • et al.
      Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study.
      FA monitoring patterns are rarely explored in real-world studies in this therapy area.
      • Holekamp N.M.
      • Liu Y.
      • Yeh W.S.
      • et al.
      Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.
      ,
      • Kiss S.
      • Liu Y.
      • Brown J.
      • et al.
      Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.
      Anti-VEGF treatment regimens using individualized, variable-interval dosing, such as PRN regimens based on findings of exudation, or treat-and-extend regimens that gradually extend assessment and treatment intervals after exudation is controlled, are used widely today. According to the American Society of Retina Specialists’ 2019 Global Trends in Retina survey, 87% of United States retina specialists favor treat-and-extend dosing for nAMD.
      American Society of Retina Specialists
      Global trends in retina.
      However, to achieve levels of VA improvement approaching those obtained with fixed monthly dosing, evidence from clinical trials suggests that variable-interval dosing regimens should include standardized OCT examinations and strict retreatment criteria based on anatomic factors (macular thickness, new hemorrhage, or new active choroidal neovascularization).
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      ,
      • Wykoff C.C.
      • Croft D.E.
      • Brown D.M.
      • et al.
      Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results.
      ,
      • Fung A.E.
      • Lalwani G.A.
      • Rosenfeld P.J.
      • et al.
      An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
      ,
      • Berg K.
      • Pedersen T.R.
      • Sandvik L.
      • Bragadóttir R.
      Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol.
      The injection frequencies revealed in the present analysis of real-world retina practice (mean, 5.8–6.1 injections in the first 12 months) are similar to those used in several prospective clinical trials of PRN ranibizumab, such as Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PRONTO) (5.6 injections),
      • Fung A.E.
      • Lalwani G.A.
      • Rosenfeld P.J.
      • et al.
      An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
      SUSTAIN (5.6 injections),
      • Holz F.G.
      • Amoaku W.
      • Donate J.
      • et al.
      Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study.
      and CATT (6.9 injections),
      • Martin D.F.
      • Maguire M.G.
      • et al.
      CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      yet despite the close similarity in age, gender, and baseline VA among the various patient populations, the VA gains seen in this analysis (mean, ≤1.6 letters at 12 months) are considerably less favorable than those achieved in the clinical trials (mean, 3.6–9.3 ETDRS letters), suggesting possible differences in disease characteristics and/or retreatment criteria between the clinical practice and clinical trial settings.
      In the real-world setting, anti-VEGF treatment outcomes are likely to be affected adversely not only by the low frequency of dosing and OCT monitoring
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study.
      but also by delays in starting anti-VEGF therapy after the initial diagnosis and by poor adherence to recommended retreatment criteria after the initial loading phase.
      • Cohen S.Y.
      • Mimoun G.
      • Oubraham H.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
      ,
      • Kumar A.
      • Sahni J.N.
      • Stangos A.N.
      • et al.
      Effectiveness of ranibizumab for neovascular age-related macular degeneration using clinician-determined retreatment strategy.
      Given that anatomic changes indicative of nAMD recurrence can in many cases be detected with OCT before the onset of vision deterioration,
      • Holz F.G.
      • Korobelnik J.F.
      • Lanzetta P.
      • et al.
      The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model.
      ,
      • Muether P.S.
      • Hermann M.M.
      • Viebahn U.
      • et al.
      Vascular endothelial growth factor in patients with exudative age-related macular degeneration treated with ranibizumab.
      it could be argued that the predominantly VA-driven retreatment criteria used in clinical practice are likely insufficient to detect early disease recurrence and optimize long-term outcomes.
      • Wolf A.
      • Kampik A.
      Efficacy of treatment with ranibizumab in patients with wet age-related macular degeneration in routine clinical care: data from the COMPASS health services research.
      The interval between diagnosis of nAMD and first anti-VEGF injection is also a key determinant of outcome,
      • Cohen S.Y.
      • Mimoun G.
      • Oubraham H.
      • et al.
      Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
      with patients who start treatment early in the disease process or with minimal delay after diagnosis being more likely to have better baseline VA and hence better treatment outcomes.
      • Shona O.
      • Gupta B.
      • Vemala R.
      • Sivaprasad S.
      Visual acuity outcomes in ranibizumab-treated neovascular age-related macular degeneration; stratified by baseline vision.
      Additionally, patients encountered in clinical practice are likely to be more heterogeneous clinically than patients participating in randomized controlled trials, which may limit the scope for vision improvement. In particular, real-world cohorts may include eyes with foveal damage and subfoveal hemorrhage, eyes with geographic atrophy or fibrosis, or eyes with very large lesions, which are usually excluded from clinical trials.
      Multiple socioeconomic factors are likely to contribute to the low use of anti-VEGF treatment and monitoring among nAMD patients in clinical practice. These patients are predominantly elderly and hence more likely to be subject to multimorbidities, physical disabilities, and transportation issues, making regular and frequent attendance at ophthalmology clinics difficult.
      • Wolf A.
      • Kampik A.
      Efficacy of treatment with ranibizumab in patients with wet age-related macular degeneration in routine clinical care: data from the COMPASS health services research.
      ,
      • Lim J.H.
      • Wickremasinghe S.S.
      • Xie J.
      • et al.
      Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration.
      From the healthcare provider’s perspective, the risks and costs associated with repeated intravitreal injections, logistic problems of large patient volumes, issues of treatment reimbursement, and low expectations of likely vision gain are factors that may discourage more frequent anti-VEGF dosing and monitoring.
      • Eldem B.
      • Lai T.Y.Y.
      • Ngah N.F.
      • et al.
      An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.
      ,
      • Holz F.G.
      • Tadayoni R.
      • Beatty S.
      • et al.
      Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study.
      .
      • Wolf A.
      • Kampik A.
      Efficacy of treatment with ranibizumab in patients with wet age-related macular degeneration in routine clinical care: data from the COMPASS health services research.
      ,
      • 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.
      The strength of the present study lies in its large sample size of more than 30 000 patients, which makes this currently the largest combined analysis of morphologic and functional outcomes of anti-VEGF therapy among nAMD patients in routine clinical practice in the United States. Study inclusion was confined to eyes that were treatment naïve and free of concomitant retinal disease, thereby replicating key selection criteria adopted for most prospective trials. Additional study attributes included the selection of a geographically and clinically disparate cohort of patients receiving treatment under different reimbursement scenarios and the use of prospectively gathered data from a large EHR system. Limitations inherent to a study based on EHRs include potential shortcomings in the accuracy and completeness of the data entered into the system. Substantial proportions of enrolled eyes were missing either baseline (36%) or 12-month (56%) VA readings, and hence only a minority provided comprehensive data at the 2 time points for direct assessment of VA change over time. Incomplete data acquisition is a frequent drawback when conducting real-world studies of treatment outcomes in retinal disease. In keeping with our findings, a recent IRIS registry study of real-world vision outcomes in nAMD reported that 35% of anti-VEGF–treated eyes recorded in this EHR database lacked baseline and 12-month VA data.
      • Rao P.
      • Lum F.
      • Wood K.
      • et al.
      Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry.
      Measures to address the issue may include excluding patients with incomplete data records from study participation or confining study analyses to patient cohorts with fully available data.
      In conclusion, the relatively low anti-VEGF injection frequencies together with the modest anatomic and suboptimal functional outcomes revealed by this analysis of USRetina data suggest that scope exists for improvement in the management of nAMD in clinical practice.

      Acknowledgments

      This study was sponsored by Allergan plc, Dublin, Ireland. Writing assistance in preparing a manuscript draft for the authors to edit was provided by Andrew Fitton, PhD, Evidence Scientific Solutions, Horsham, UK, and was funded by Allergan plc, Irvine, CA.

      Supplementary Data

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