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Figure 1.
Costs During 1 Year Divided Into Study and Nonstudy Eye Anti–Vascular Endothelial Growth Factor (VEGF) Injections Separately, Laser Photocoagulation, and Adverse Events
Costs During 1 Year Divided Into Study and Nonstudy Eye Anti–Vascular Endothelial Growth Factor (VEGF) Injections Separately, Laser Photocoagulation, and Adverse Events

Costs are presented for all participants and the worse and better visual acuity (VA) subgroups. Anti-VEGF injections include the agent costs and a $102.97 fee per injection.

Figure 2.
The Aflibercept-Bevacizumab Incremental Cost-effectiveness Ratio (ICER) for Varying Assumptions for Visual Acuity (VA) Changes in 10 Years
The Aflibercept-Bevacizumab Incremental Cost-effectiveness Ratio (ICER) for Varying Assumptions for Visual Acuity (VA) Changes in 10 Years

The changing color indicates the 10-year ICER based on VA change with each drug. BCVA indicates best-corrected VA; ETDRS, Early Treatment Diabetic Retinopathy Study letter score.

Table 1.  
Cost-effectiveness Outcomes
Cost-effectiveness Outcomes
Table 2.  
Cost Thresholds for Ranibizumab and Aflibercept
Cost Thresholds for Ranibizumab and Aflibercept
1.
Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.  N Engl J Med. 2015;372(13):1193-1203.PubMedGoogle ScholarCrossref
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Red Book Online [database online]. Greenwood Village, CO: Truven Health Analytics Inc; 2016.
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US Department of Health and Human Services, Office of Inspector General.  Medicare payments for drugs used to treat wet age-related macular degeneration. Washington, DC: US Dept of Health and Human Services; 2012. Publication OEI-03-10-00360.
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Elman  MJ, Ayala  A, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.  Ophthalmology. 2015;122(2):375-381.PubMedGoogle ScholarCrossref
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US Government Accountability Office.  Medicare Part B: Expenditures for new drugs concentrated among a few drugs, and most were costly for beneficiaries. Washington, DC: US Government Accountability Office; 2015:QAO-16-12.
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Brown  MM, Brown  GC, Sharma  S, Landy  J.  Health care economic analyses and value-based medicine.  Surv Ophthalmol. 2003;48(2):204-223.PubMedGoogle ScholarCrossref
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Thulliez  M, Angoulvant  D, Le Lez  ML,  et al.  Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis.  JAMA Ophthalmol. 2014;132(11):1317-1326.PubMedGoogle ScholarCrossref
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Pershing  S, Enns  EA, Matesic  B, Owens  DK, Goldhaber-Fiebert  JD.  Cost-effectiveness of treatment of diabetic macular edema.  Ann Intern Med. 2014;160(1):18-29.PubMedGoogle ScholarCrossref
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Stein  JD, Newman-Casey  PA, Kim  DD, Nwanyanwu  KH, Johnson  MW, Hutton  DW.  Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema.  Ophthalmology. 2013;120(9):1835-1842.PubMedGoogle ScholarCrossref
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Bonafede  MM, Johnson  BH, Richhariya  A, Gandra  SR.  Medical costs associated with cardiovascular events among high-risk patients with hyperlipidemia.  Clinicoecon Outcomes Res. 2015;7:337-345.PubMedGoogle ScholarCrossref
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Frick  KD, Gower  EW, Kempen  JH, Wolff  JL.  Economic impact of visual impairment and blindness in the United States.  Arch Ophthalmol. 2007;125(4):544-550.PubMedGoogle ScholarCrossref
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Mitchell  P, Annemans  L, Gallagher  M,  et al.  Cost-effectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment: evidence from the RESTORE trial.  Br J Ophthalmol. 2012;96(5):688-693.PubMedGoogle ScholarCrossref
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Grosse  SD.  Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold.  Expert Rev Pharmacoecon Outcomes Res. 2008;8(2):165-178.PubMedGoogle ScholarCrossref
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Anderson  JL, Heidenreich  PA, Barnett  PG,  et al.  ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines.  J Am Coll Cardiol. 2014;63(21):2304-2322.PubMedGoogle ScholarCrossref
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Hutton  D, Newman-Casey  PA, Tavag  M, Zacks  D, Stein  J.  Switching to less expensive blindness drug could save Medicare Part B $18 billion over a ten-year period.  Health Aff (Millwood). 2014;33(6):931-939.PubMedGoogle ScholarCrossref
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Neumann  PJ, Cohen  JT, Weinstein  MC.  Updating cost-effectiveness: the curious resilience of the $50,000-per-QALY threshold.  N Engl J Med. 2014;371(9):796-797.PubMedGoogle ScholarCrossref
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Ubel  PA, Hirth  RA, Chernew  ME, Fendrick  AM.  What is the price of life and why doesn’t it increase at the rate of inflation?  Arch Intern Med. 2003;163(14):1637-1641.PubMedGoogle ScholarCrossref
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Brown  DM, Schmidt-Erfurth  U, Do  DV,  et al.  Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies.  Ophthalmology. 2015;122(10):2044-2052.PubMedGoogle ScholarCrossref
19.
Nguyen  QD, Brown  DM, Marcus  DM,  et al; RISE and RIDE Research Group.  Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.  Ophthalmology. 2012;119(4):789-801.PubMedGoogle ScholarCrossref
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Elman  MJ, Bressler  NM, Qin  H,  et al; Diabetic Retinopathy Clinical Research Network.  Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2011;118(4):609-614.PubMedGoogle ScholarCrossref
Original Investigation
August 2016

Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment: Analysis From the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial

Author Affiliations
  • 1Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor
  • 2Department of Health Management and Policy, University of Michigan School of Public Health, Ann Arbor
  • 3Department of Industrial and Operations Engineering, University of Michigan College of Engineering, Ann Arbor
  • 4Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor
  • 5Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 6Editor, JAMA Ophthalmology
  • 7Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 8Jaeb Center for Health Research, Tampa, Florida
JAMA Ophthalmol. 2016;134(8):888-896. doi:10.1001/jamaophthalmol.2016.1669
Abstract

Importance  Anti–vascular endothelial growth factor (VEGF) medicines have revolutionized diabetic macular edema (DME) treatment. A recent randomized clinical trial comparing anti-VEGF agents for patients with decreased vision from DME found that at 1 year aflibercept (2.0 mg) achieved better visual outcomes than repackaged (compounded) bevacizumab (1.25 mg) or ranibizumab (0.3 mg); the worse the starting vision, the greater the treatment benefit with aflibercept. However, aflibercept and ranibizumab, respectively, are approximately 31 and 20 times more expensive than bevacizumab.

Objective  To examine the incremental cost-effectiveness ratios (ICERs) of aflibercept, bevacizumab, and ranibizumab for the treatment of DME.

Design, Setting, and Participants  Post hoc analysis of efficacy, safety, and resource utilization data at 1-year follow-up from the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. Patients were enrolled from August 22, 2012, through August 28, 2013, and analysis was performed from August 21, 2014, through November 7, 2015.

Main Outcomes and Measures  The ICERs for all trial participants and subgroups with baseline vision of approximate Snellen equivalent 20/32 to 20/40 (better vision) and baseline vision of approximate Snellen equivalent 20/50 or worse (worse vision). One-year trial data were used to calculate cost-effectiveness for 1 year for the 3 anti-VEGF agents; mathematical modeling was then used to project 10-year cost-effectiveness results.

Results  The study included 624 participants (mean [SD] age, 60.6 [10.5] years; 45.7% female; 65.5% white), 209 in the aflibercept group, 207 in the bevacizumab group, and 208 in the ranibizumab group. For all participants, during 1 year, the ICERs of aflibercept and ranibizumab compared with bevacizumab were $1 110 000 per quality-adjusted life-year (QALY) and $1 730 000 per QALY, respectively. During 10 years, they were $349 000 per QALY and $603 000 per QALY, respectively. Compared with ranibizumab, aflibercept’s ICER was $648 000 per QALY at 1 year and $203 000 per QALY at 10 years. For the subgroup with worse baseline vision, the 10-year ICERs of aflibercept and ranibizumab compared with bevacizumab were $287 000 per QALY and $817 000 per QALY, respectively. In eyes with decreased vision from DME, treatment costs of aflibercept and ranibizumab would need to decrease by 69% and 80%, respectively, to reach a cost-effectiveness threshold of $100 000 per QALY compared with bevacizumab during a 10-year horizon; for the subgroup with worse baseline vision, the costs would need to decrease by 62% and 84%, respectively.

Conclusions and Relevance  Aflibercept (2.0 mg) and ranibizumab (0.3 mg) are not cost-effective relative to bevacizumab for treatment of DME unless their prices decrease substantially. These results highlight the challenges that physicians, patients, and policymakers face when safety and efficacy results are at odds with cost-effectiveness results.

Introduction

Quiz Ref IDA recent Diabetic Retinopathy Clinical Research Network (DRCR.net) comparative effectiveness trial found that for patients with diabetic macular edema (DME) and approximate Snellen equivalent baseline visual acuity (VA) of 20/50 or worse aflibercept produced greater mean VA gains at 1 year than bevacizumab or ranibizumab. In contrast, no difference in mean VA improvement was identified for patients with baseline VAs of 20/32 to 20/40.1

These agents also vary substantially in cost. On the basis of 2015 wholesale acquisition costs, aflibercept (2.0 mg) costs $1850,2 ranibizumab (0.3 mg) costs $1170,2 and bevacizumab repackaged at compounding pharmacies into syringes for ophthalmologic use containing 1.25 mg of bevacizumab costs approximately $60 per dose.3 Considering that these medicines may be given 9 to 11 times in the first year of treatment1 and, on average, 17 times during 5 years,4 total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of anti–vascular endothelial growth factor (VEGF) therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget.3 In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.5 Given these costs, the DRCR.net investigators believed it was important to analyze the relative cost-effectiveness of treating DME using each agent.

Box Section Ref ID

Key Points

  • Question What is the incremental cost-effectiveness of different anti–vascular endothelial growth factor therapies over bevacizumab for the treatment of diabetic macular edema?

  • Findings Visual acuity benefits of aflibercept and ranibizumab translate into modest quality-of-life improvements but at a high cost relative to bevacizumab, with incremental cost-effectiveness ratios substantially higher than frequently cited thresholds (eg, $100 000 per quality-adjusted life-year).

  • Meaning Physicians and policymakers should keep in mind these results when considering the incremental cost-effectiveness of these agents compared with bevacizumab.

Methods
Overview

Quiz Ref IDIn a post hoc analysis, data from a randomized clinical trial were used to calculate clinical benefit, costs, and cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for DME.1 With the use of published cost and quality-of-life data, resource utilization and VA results from the trial were converted into estimates of overall medical costs and quality-adjusted life-years (QALYs) accrued during the first year of the trial.6 A mathematical model projected longer-term costs and health outcomes with each therapy (eMaterial in Supplement). Each therapy’s incremental cost-effectiveness ratio (ICER) was calculated, defined as the ratio of its incremental cost (in 2015 US $) to its incremental benefit (in QALYs) compared with the next-best therapy. Future outcomes were discounted at an annual rate of 3% to reflect their present value.

Because treatment efficacy in the DRCR.net trial differed significantly by baseline VA, the cost-effectiveness of these therapies also was assessed for better (approximate Snellen equivalent of 20/32-20/40 [Early Treatment Diabetic Retinopathy Study letter score of 78-69]) and worse (approximately 20/50 or worse [letter score <69]) VA subgroups.

Participants

The DRCR.net Protocol T trial included 660 patients randomized to aflibercept, bevacizumab, or ranibizumab for treatment of DME. Patients were enrolled from August 22, 2012, through August 28, 2013; this analysis was performed from August 21, 2014, through November 7, 2015. The study adhered to the Declaration of Helsinki and was approved by local and centralized institutional review boards. Detailed procedures, protocol, and statistical methods have been reported previously.1 All study participants provide written informed consent.

Participants were 18 years or older and had 1 study eye with VA (Snellen equivalent) of 20/32 to 20/320 attributable to DME. Among the 660 participants, 329 eyes (49.8%) were in the worse VA subgroup, and 331 (50.1%) in the better VA subgroup. Patients were followed up every 4 weeks (termed monthly hereafter) for 1 year, with anti-VEGF injections provided on a monthly basis for the first 6 months in most cases. Thereafter, treatment was deferred if the eye was stable; laser treatment was added, if indicated, based on study-defined criteria. After deferring injections, if VA or macular thickness worsened because of DME, injections resumed until stability again occurred. If a participant’s nonstudy eye also required anti-VEGF treatment during the trial, it was given the same agent as the study eye. Participants were excluded for unavailable for follow-up (not including deaths) before the 1-year visit (n = 29) or receiving an anti-VEGF agent other than randomized to receive (n = 7), leaving a total of 624 participants.

Quality of Life

Participant VA levels at each visit were converted to QALYs using data from Brown et al,6 who linked VA in a patient’s better-seeing eye with health-related quality of life. The VAs were obtained from the trial, converted to Snellen acuities, and assigned a utility based on conversion tables. Quality-of-life levels at monthly visits during the first year were summed, providing an aggregate QALY value for the entire year for each participant.

Calculated quality of life was reduced for participants experiencing adverse events possibly caused by the study agent, including myocardial infarction, cerebrovascular accident, endophthalmitis, retinal detachment, and vitreous hemorrhage. Both myocardial infarction and cerebrovascular accident were assumed to reduce quality of life for the remainder of one’s life; other adverse events resulted in one-time quality-of-life decrements (eTable 1 in the Supplement). During the 1-year trial horizon, adverse events were identified and incorporated into the analysis based on patient-level trial data, differing nominally among the treatment arms. Because a difference in adverse event rates and mortality among the treatment arms was not identified at 1 year in the trial or previous meta-analyses,1,7 the same pooled rates were used for all anti-VEGF agents in modeling projections beyond 1 year.

To assess cost-effectiveness beyond 1 year, a mathematical model based on prior cost-effectiveness analyses for DME was developed (eFigure 1 in the Supplement).8,9 A prior trial using ranibizumab for DME found relatively stable mean VAs 1 to 5 years after treatment initiation4; accordingly, the model assumes a patient’s VA at 1 year remains constant throughout the remainder of the patient’s life, with ongoing monitoring and anti-VEGF therapy as needed. This assumption was varied widely in sensitivity analyses.

Costs

Overall costs were calculated by applying standardized unit costs to treatment and adverse event data from the trial, specifically including adverse events and treatments with the potential to vary among the treatment arms (eTable 2 and eTable 3 in the Supplement). Injection costs were based on the average wholesale prices of each anti-VEGF agent and Medicare physician fees for administration in an office-based setting. Because trial protocol dictated that participants requiring treatment in the nonstudy eye receive the same agent as the study eye, which could potentially affect quality-of-life outcomes, we included costs for both study eye and nonstudy eye treatments. Adverse event costs were based on studies10,11 of long-term costs of myocardial infarction, cerebrovascular accident, and legal blindness. Costs not expected to vary among the treatment arms were not captured, including office visit costs, unrelated medical costs, and indirect costs, such as caregiver burden. Thus, this analysis provides an accurate estimate of incremental costs among the treatment arms but not of overall medical costs associated with DME. Five-year data from a prior trial4 using ranibizumab were used to estimate the decreasing rates of injection and laser treatment during the longer term (eTable 1 in the Supplement).

Statistical Analysis

Unpaired, 2-tailed t tests assessed the significance of cost and quality-of-life differences in 1-year data from the trial. Calculated P values reflect subject-level variance from trial data but do not account for uncertainty in unit cost or quality-of-life data from outside sources.

Sensitivity Analyses

To assess robustness of these results and explore how different assumptions might affect cost-effectiveness of the therapies, several sensitivity analyses were performed. In univariate and bivariate sensitivity analyses, effects of varying 1 or 2 key parameters at a time were assessed. In the base case analysis, quality of life was mapped to visual acuity in the patient’s better-seeing eye; a sensitivity analysis used data from the UK-based Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial of anti-VEGF therapy for DME to map quality of life to VA in the patient’s treated eye (whether it was the better- or worse-seeing eye).12 The effects of varying the time horizon of the modeling projections (1-30 years), changes in VA achieved from using the 3 agents for 10 years (±20 letters), adverse event rates (0%-100% of base case), and others were explored. Costs of aflibercept and ranibizumab were varied to determine at what prices they would have an ICER below $100 000 per QALY, a threshold commonly considered meaningful for determining cost-effectiveness in the United States.13-17

To assess uncertainty in model inputs, a probabilistic sensitivity analysis was performed. Synthetic trial treatment groups were created by randomly drawing 200 participants from each trial arm, with replacement; values for model parameters, including costs, quality of life, and adverse event rates, then were drawn at random from distributions, reflecting their uncertainty. This process was repeated 10 000 times with cost-effectiveness results calculated for each iteration to obtain a distribution of probabilities for each treatment strategy to be cost-effective at different societal willingness-to-pay values per QALY.

Results
Quality of Life

The study included 624 participants (mean [SD] age, 60.6 [10.5] years; 45.7% female; 65.5% white), 209 in the aflibercept group, 207 in the bevacizumab group, and 208 in the ranibizumab group. For the aflibercept, bevacizumab, and ranibizumab arms, respectively, the mean QALYs (Table 1) were 0.869 (95% CI, 0.857-0.880), 0.849 (95% CI, 0.835-0.862), and 0.857 (95% CI, 0.843-0.872) during the first year of the trial; 0.835 (95% CI, 0.817-0.854), 0.823 (95% CI, 0.807-0.840), and 0.829 (95% CI, 0.813-0.846) for participants with worse baseline vision; and 0.901 (95% CI, 0.891-0.911), 0.875 (95% CI, 0.855-0.895), and 0.884 (95% CI, 0.861-0.907) for those with better baseline vision (Table 1). Differences in mean QALYs among the treatment arms were largest for aflibercept vs bevacizumab among all participants (P = .03) (eTable 4 in the Supplement) and aflibercept vs bevacizumab among those with better baseline vision (P = .02) (eTable 4 in the Supplement). All other comparisons had P > .15 (eTable 4 in the Supplement).

Of note, these outcomes may appear at odds with original trial results indicating the greatest VA benefit of aflibercept vs bevacizumab among the worse baseline vision group. This difference reflects the nonlinear association between VA and quality of life, as well as the fact that QALYs were summed for each month in this analysis, whereas VA was compared only at 1 year in the original trial (eMaterial in the Supplement).

Resources and Costs

Total mean costs per participant during 1 year (including study eye and nonstudy eye anti-VEGF injections, laser photocoagulation, and adverse events) in the aflibercept, bevacizumab, and ranibizumab groups, respectively, were $26 100 (95% CI, $24 400-27 700), $4100 (95% CI, $3000-5200), and $18 600 (95% CI, $17 100-20 200) (all differences P < .001) (Figure 1). Anti-VEGF injections include the agent costs and a $102.97 fee per injection. Overall mean costs were higher for those with worse baseline vision ($28 100, $5000, and $20 400, respectively) and lower for those with better baseline vision ($24 100, $3200, and $16 900, respectively).

The largest component of total cost was study eye anti-VEGF injections, comprising 68%, 37%, and 63% of total cost in the aflibercept, bevacizumab, and ranibizumab groups, respectively (Figure 1). Regardless of baseline vision, study eye anti-VEGF injection costs were higher with aflibercept compared with bevacizumab or ranibizumab and with ranibizumab compared with bevacizumab (all differences P < .001). A difference in cost for adverse events or laser photocoagulation was not identified among the treatment arms for any of the baseline vision subgroups.

One-Year Cost-effectiveness

For all participants, the ICERs of aflibercept and ranibizumab compared with bevacizumab were $1 110 000 per QALY and $1 730 000 per QALY, respectively (Table 1). For the subgroup with worse baseline vision, the ICERs were $1 870 000 per QALY and $2 450 000 per QALY; with better baseline vision, they were $798 000 per QALY and $1 500 000 per QALY. The ICER of aflibercept compared with ranibizumab was $648 000 per QALY for all participants, $1 270 000 per QALY for the worse baseline vision subgroup, and $422 000 per QALY for the better baseline vision subgroup.

Longer-term Projections

Quiz Ref IDThe mathematical model of longer-term results produced similar 3-year adverse event rates, 5-year survival, and life expectancy to other published studies of similar populations, supporting the validity of these projections (eTable 5 in the Supplement).10-12 Projected during a 10-year horizon, among all participants, the worse baseline vision subgroup, and the better baseline vision subgroup, respectively, the difference in QALYs with aflibercept vs bevacizumab was 0.18, 0.22, and 0.13 (Table 1). Among all participants, the worse baseline vision subgroup, and the better baseline vision subgroup, respectively, the ICERs of aflibercept and ranibizumab vs bevacizumab were $349 000 per QALY and $603 000 per QALY, $287 000 per QALY and $817 000 per QALY, and $474 000 per QALY and $506 000 per QALY (Table 1). Among all participants, the worse baseline vision subgroup, and the better baseline vision subgroup, respectively, the ICER of aflibercept vs ranibizumab was $203 000 per QALY, $135 000 per QALY, and $428 000 per QALY.

Drug Cost Thresholds

Table 2 indicates how much the drug costs of aflibercept and ranibizumab would need to be reduced for them to become cost-effective ($100 000 per QALY) relative to bevacizumab. Across varying time horizons and baseline vision subgroups, the per-dose cost of aflibercept would need to decrease by 60% to 90%. Considering all patients, those with worse baseline vision, and those with better baseline vision, respectively, the cost per dose of aflibercept would need to decrease below $240, $250, or $230 (vs a current cost of $1850) to become cost-effective relative to bevacizumab during 1 year and below $570, $700, or $410 for the same 3 groups during a 10-year horizon. Ranibizumab would require even larger cost decreases to become cost-effective relative to bevacizumab (75%-95%, depending on the subgroup and the time horizon). eTable 6 and eTable 7 in the Supplement give the costs required to reach alternative cost-effectiveness thresholds of $50 000 per QALY and $150 000 per QALY. When compared with ranibizumab, aflibercept’s cost would need to be reduced by 18% considering all patients, 9% for those with worse baseline vision, and 28% for those with better baseline vision to reach a cost-effectiveness threshold of $100 000 per QALY at 10 years (eTable 8 in the Supplement). eTable 9 in the Supplement gives the 10-year ICERs for a wide range of costs for aflibercept or ranibizumab.

Sensitivity Analyses

In univariate sensitivity analyses, varying the time horizon (eFigure 2 in the Supplement), adverse event rates with the 3 drugs (eFigure 3 in the Supplement), longer-term anti-VEGF injection frequency (eFigure 4 in the Supplement), and the methods used to convert vision into quality of life (eTable 10 in the Supplement), aflibercept and ranibizumab never reached an ICER below $100 000 per QALY compared with bevacizumab.

Because quality-of-life benefits of treatment were linked to vision in the better-seeing eye in the base case analysis, a subgroup of only those with better vision in the study eye vs the nonstudy eye was examined. In this subgroup, the ICERs of aflibercept and ranibizumab, respectively, compared with bevacizumab were $467 000 per QALY and $603 000 per QALY at 1 year and $210 000 per QALY and $231 000 per QALY at 10 years.

When simulating variable long-term VA outcomes, aflibercept reached an ICER below $100 000 per QALY relative to bevacizumab only if aflibercept had unrealistic long-term gains in VA and bevacizumab had losses (Figure 2). For instance, if aflibercept produced a 12-letter mean gain in VA during years 2 to 10 of treatment and bevacizumab produced a 13-letter mean loss, then aflibercept would have an ICER below $100 000 per QALY relative to bevacizumab. For aflibercept to reach an ICER below $100 000 per QALY compared with ranibizumab at 10 years, it would require additional mean VA gains of at least 5 letters relative to ranibizumab for years 2 to 10 (eFigure 5 in the Supplement).

A probabilistic sensitivity analysis assessed overall uncertainty in patient outcomes and parameter assumptions. eFigure 6 in the Supplement shows the resulting estimates of the likelihood that each treatment will be optimal (ie, cost-effective), defined as producing the greatest QALYs while maintaining an ICER below a set willingness to pay per QALY. During a 1-year horizon, there was a greater than 95% likelihood that bevacizumab would be the optimal therapy, irrespective of baseline vision, as long as willingness to pay is less than $530 000 per QALY. During a 10-year horizon, bevacizumab would have a greater than 90% likelihood of being optimal at a willingness to pay $100 000 per QALY, irrespective of baseline VA. For the subgroup of patients with worse baseline vision, during a 10-year horizon aflibercept is more likely to be optimal than bevacizumab or ranibizumab at willingness-to-pay values of $230 000 per QALY or greater.

Discussion

In the first year results of a DRCR.net trial in eyes with VAs of 20/50 or worse because of DME, aflibercept produced greater mean VA gains compared with bevacizumab or ranibizumab. The current analysis suggests that the VA benefits of aflibercept translate into modest quality-of-life improvements but at a high cost relative to bevacizumab, with the ICERs substantially higher than thresholds of $50 000 to $150 000 per QALY frequently cited in cost-effectiveness literature and US guidelines. They remain above these threshold values even under broad alternative assumptions. It is unlikely that any realistic differences in VA achieved with the 3 agents during years 2 to 10 (in the range of changes seen in prior studies1,4,18-20) would alter their relative cost-effectiveness.

With rapidly increasing US health care costs and given the widely varying costs of intravitreous anti-VEGF agents, it seems important that payers, policymakers, and physicians consider both the costs and benefits of these agents. This analysis demonstrates that, from the payer or policymaker perspective, using bevacizumab rather than the more expensive agents would be cost-effective. Similarly, in contexts where bevacizumab is not available, 0.3 mg of ranibizumab would be more cost-effective than aflibercept.

From the perspective of patients or physicians, however, the decision seems less clear-cut. For some patients with DME, the expected additional visual benefits conferred by aflibercept compared with bevacizumab at 1 year or the perceived concerns over repackaging risks or lack of a US Food and Drug Administration indication with bevacizumab may outweigh the added health system cost ($22 000 at 1 year) and may outweigh any added personal expenses, such as copayments. This tension highlights the challenge of balancing varying perspectives of patients, physicians, payers, and policymakers when efficacy results and cost-effectiveness are at odds or when inconsistent comparative safety results across these agents are reported in the literature.

Quiz Ref IDStudy limitations include using trial data only through 1 year of follow-up; longer-term results relied on outside data sources and mathematical modeling. However, sensitivity analyses indicate that results beyond 1 year would have to be strikingly different from prior data on long-term anti-VEGF outcomes1,4,18-20 to alter the study findings. Next, the bevacizumab in this trial was repackaged or compounded into sterile vials, which might cost more than typical costs of repackaging. However, even if the price per bevacizumab dose was raised to $710, such that a whole 4-mL container is used for every injection with the excess discarded,2 thus forgoing the need for repackaging, bevacizumab remains the most cost-effective option (eTable 9 in the Supplement). In addition, quality-of-life outcomes were based on VA outcomes and prior data relating VA to quality of life; although VA is a reliable predictor of quality of life, direct measurement of quality of life still would be preferable.6 Patient-specific factors, such as VA in the untreated eye, also could alter cost-effectiveness results for an individual patient. It is important to exercise caution in applying these results to other countries; although the data indicate that aflibercept and ranibizumab are not cost-effective in the United States, differing cost structures or lower negotiated prices may alter their cost-effectiveness in other health care systems.

Conclusions

Aflibercept (2.0 mg) and ranibizumab (0.3 mg) are not cost-effective relative to bevacizumab for treatment of DME unless their prices decrease substantially. Likewise, in contexts where bevacizumab is unavailable for DME treatment, aflibercept is not cost-effective relative to ranibizumab. From a societal perspective, bevacizumab as first-line therapy for DME would confer the greatest value, along with substantial cost savings vs the other agents. These results highlight the challenges that physicians, patients, and policymakers face when safety and efficacy results are at odds with cost-effectiveness results.

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Article Information

Submitted for Publication: January 29, 2016; final revision received April 11, 2016; accepted April 12, 2016.

Corresponding Author: Adam R. Glassman, MS, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrstat2@jaeb.org).

Published Online: June 9, 2016. doi:10.1001/jamaophthalmol.2016.1669.

Author Contributions: Mr Ross and Dr Hutton had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Ross, Hutton, Stein, Bressler, Jampol.

Drafting of the manuscript: Ross, Hutton, Stein, Jampol.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ross, Hutton,.

Obtained funding: Bressler, Jampol, Glassman.

Administrative, technical, or material support: Ross, Hutton, Bressler, Glassman.

Study supervision: Hutton, Bressler, Glassman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hutton reported receiving grants from Jaeb Center for Health Research during the conduct of the study. Dr Bressler reported receiving grants from the National Institutes of Health, Regeneron, and Genentech/Roche during the conduct of the study and grants from Bayer and Novartis outside the submitted work. Dr Glassman reported receiving grants from the Regeneron, and Genentech/Roche during the conduct of the study. No other disclosures were reported. A complete list of all Diabetic Retinopathy Clinical Research Network (DRCR.net) financial disclosures can be found at http://www.drcr.net.

Funding/Support: This study was supported by grants EY14231 (Mr Glassman), EY23207 (Dr Jampol), and EY18817 (Dr Bressler) through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services.

Role the Funder/Sponsor: The National Institutes of Health participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. Regeneron provided the aflibercept for protocol T. Genentech provided the ranibizumab for Protocol T and funds to DRCR.net to defray the study’s clinical site costs. As per the DRCR.net Industry Collaboration Guidelines (available at http://www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.

Group Information: The following Diabetic Retinopathy Clinical Research Network clinical sites participated in this protocol. Sites are listed in order by number of subjects enrolled into the study. The number of subjects enrolled is noted in parenthesis preceded by the site location and the site name. Personnel are listed as (I) for study investigator, (C) for coordinator, (V) visual acuity technician, and (P) for photographer. Charlotte, North Carolina, Charlotte Eye, Ear, Nose and Throat Associates, PA (50): David Browning (I); Andrew N. Antoszyk (I); Angela K. Price (C, V); Sherry L. Fredenberg (C, V); Jenna T. Herby (C, V); Christina J. Fleming (C, V); Ashley A. McClain (C, V); Sarah A. Ennis (V); Kelly R. Gallagher (V); Angella S. Karow (V); Autumn C. Grupp (V); Danielle Puskas (P); Lynn Watson (P); Swann J. Bojaj (P); Uma M. Balasubramaniam (P); Donna McClain (P); Donna R. Styles (P); Jeff A. Kuopus (P); Kathryn Kimrey (P); Loraine M. Clark (P); Lisa A. Jackson (P); Michael D. McOwen (P); Matt Dunlap (P); Susannah J. Held (P), Santa Barbara, California: California Retina Consultants (28): Dante J. Pieramici (I); Ma'an A. Nasir (I); Alessandro A. Castellarin (I); Dilsher Dhoot (I); Sarah Fishbein (C, V); Jack Giust (C); Lisha Wan (C, V); Michelle S. Hanna (C, V); Melvin D. Rabena (C); Jerry Smith (V); Layne J. Bone (V); Kelly Avery (V); Matthew Giust (P); Aimee Walker (P); Aimee H. Shook (P); Sara Esau (P); Nitce L. Ruvalcaba (P); West Columbia, South Carolina: Palmetto Retina Center (28): John A. Wells (I); W. Lloyd Clark (I); David L. Johnson (I); John F. Payne (I); Tiffany R. Swinford (C, V); Mallie M. Taylor (C); Cassandra L. Garrison (C); Peggy D. Miller (C, V); Amber R. Houlahan (V); Charlotte A. O'Neill (V); Ashley Floyd (V); Crystal C. Parker (V); Courtney Sease (V); Tara Graham (V); Robin Spencer (V); Tiffany N. Ogbuewu (V); Ashley Studebaker (P); Tyler Huggins (P); Robbin Spivey (P); Brian Jones (P); Ashley Williams (P); Ron Petty (P); Erin L. Poston (P); G. Michael Ward (P); Paducah, Kentucky: Paducah Retinal Center (24): Carl W. Baker (I); Ron H. Tilford (I); Tracey M. Caldwell (C); Lynnette F. Lambert (C, V); Mary J. Palmer (V); Tracey R. Martin (V); Tana R. Williams (P); Samantha Kettler (P); Alecia B. Camp (P); Boston, Massachusetts: Joslin Diabetes Center/Harvard Vanguard Medical Associates (22): Paolo S. Silva (I); Paul G. Arrigg (I); George S. Sharuk (I); Sabera T. Shah (I); Jennifer K. Sun (I); Corey Westerfeld (I); Christopher Michael Andreoli (I); Lloyd Paul Aiello (I); Deborah Schlossman (I); Timothy Murtha (I); Hanna Kwak (C); Flor M. Flores (C, V); Margaret E. Stockman (C, V); Troy Kieser (C, V); Michael N. Krigman (V); Leila Bestourous (V); Elizabeth S. Weimann (V); Jerry D. Cavallerano (V); Kristen M. Hock (V); Mary Ann Robertson (V); Rita K. Kirby (V); Steve L. Papaconstantinou (V); Kylie M. Madigan (P); Robert W. Cavicchi (P); Kate A. Palitsch (P); Taygan Yilmaz (P); Austin, Texas: Retina Research Center (20): Brian B. Berger (I); Chirag D. Jhaveri (I); Tori Moore (C); Ginger J. Manhart (C); Rachel A. Walsh (C); Ivana Gunderson (C, V); Dietrich Riepen (V); Chelsey A. Bravenec (V); Ryan M. Reid (V); Yong Ren (P); Ben Ostrander (P); Christopher C. Stovall (P); Baltimore, Maryland: Elman Retina Group, PA (18): Michael J. Elman (I); Robert A. Liss (I); Henry A. Leder (I); JoAnn Starr (C); Jennifer L. Belz (C); Charlene K. Putzulo (C); Dallas R. Sandler (V); Jennifer L. Simmons (V); Pamela V. Singletary (V); Ashley Davis (V); Perel M. Simpson (V); Teresa Coffey (V); Daniel J. Ketner (P); Terri Cain (P); Ashley M. Metzger (P); Peter Sotirakos (P); Baltimore, Maryland: Elman Retina Group PA (18): Michael J. Elman (I); Robert A. Liss (I); Henry A. Leder (I); JoAnn Starr (C); Jennifer L. Belz (C); Charlene K. Putzulo (C); Dallas R. Sandler (V); Jennifer L. Simmons (V); Pamela V. Singletary (V); Ashley Davis (V); Perel M. Simpson (V); Teresa Coffey (V); Daniel J. Ketner (P); Terri Cain (P); Ashley M. Metzger (P); Peter Sotirakos (P); Augusta, Georgia: Southeast Retina Center PC (17): Dennis M. Marcus (I); Harinderjit Singh (I); Courtney N. Roberts (C); Geri L Floyd (C); Siobhan O. Ortiz (C); Virginia Mims (V); L. Allison Foster (V); Christy Coursey (V); Jared C. Gardner (P); Ken Ivey (P); Richmond, Virginia: Retina Institute of Virginia (15): John Stewart O'Keefe (I); Juan A. Astruc (I); Bryan J. Schwent (I); Ali R. Tabassian (I); Suzette A. Rosen (C); David C. Vaughan (V); Jeffrey Michaels (V); Natalie J. Arndt (V); John J. Maziarz (P); Lakeland, Florida: Florida Retina Consultants (14): Scott M. Friedman (I); Nader Moinfar (I); Kimberly A. Williamson (C, V); Damanda F. Fagan (C, V); Katrina L. Dawson (C); Paige N. Walters (V); Allen McKinney (P); Steve Carlton (P); Salt Lake City, Utah: Retina Associates of Utah PC (14): Robert C. Kwun (I); Victoria L. Knudsen (I); Kirk E. Winward (I); Mano Swartz (I); James G. Howard (I); Michelle Riley (C); Gena Taylor (V); Michelle Holt (P); Jason G. Winward (P); Adam Walsh (P); Teresa Taylor (P); Daniel Walsh (P); Syracuse, New York: Retina-Vitreous Surgeons of Central New York, PC (13): G. Robert Hampton (I); Jamin S. Brown (I); Rajeev K. Seth (I); Laurie J. Sienkiewycz (C); Deborah A. Appleton (C); Cindy J. Grinnell (C); Charity A. Cowley (C); Lynn M. Kwasniewski (V); Michelle L. Manley (V); Nicole E. Robarge (P); Stefanie R. DeSantis (P); Peter B. Hay (P); Teresa M. DeForge (P); Houston, Texas: Retina Consultants of Houston, PA (12): Charles C. Wykoff (I); Tien P. Wong (I); Eric Chen (I); David M. Brown (I); Rosa Y. Kim (I); James C. Major (I); Amy C. Schefler (I); Richard H. Fish (I); Matthew S. Benz (I); Meredith Lipman (C); Amy Hutson (C); Nubia Landaverde (C); Ashley E. Chancey (C); Cassie Cone (C); Tressa Royse (V); Veronica A. Sneed (V); Belinda A. Almanza (V); Brenda Dives (V); Beau A Richter (P); Eric N. Kegley (P); Portland, Oregon; Casey Eye Institute (12): Andreas K. Lauer (I); Christina J Flaxel (I); Steven T. Bailey (I); Mitchell Schain (C, V); Ann D. Lundquist (C, V); Shelley A. Hanel (C); Shirley D. Ira (V); Susan K. Nolte (V); Peter N. Steinkamp (P); Dawn M. Ryan (P); Scott R. Pickell (P); Jocelyn T. Hui (P); Michelle Brix (P); Jordan Barth (P); Chris S Howell (P); Shawnee Mission, Kansas: Retina Associates PA (12): Gregory M. Fox (I); Blake A. Cooper (I); Ivan R. Batlle (I); Lexie R. Manning (C); Karla A. Batlle (C); Holly Wyrick (V); Katherine Pippin (P); Samantha Perkins (P); Frank T. Yeager (P); Amarillo, Texas: Southwest Retina Specialists (11): Ryan B. Rush (I); Glenn R. Gardner (C); Christi Rush (C); Johnathan R. Hawkins (V); Brenda Dumas (V); Ben Ysasaga (P); Boston, Massachusetts: Ophthalmic Consultants of Boston (11): Chirag P. Shah (I); Michael G. Morley (I); Torsten W. Wiegand (I); Tina S. Cleary (I); Trexler M. Topping (I); Lindsey Colegrove (C, V); Katharine Bechtel (C, V); Britta Johnson (C, V); Lisa Lebedew (V); Natacha Lorius (V); Sandy G. Chong (V); Jennifer L. Stone (V); Michael Cullen Jones (P); Dennis Donovan (P); Sherry Malone (P); Margie Graham (P); Audrey Santos (P); Steve A. Bennett (P); St Louis, Missouri: The Retina Institute (11): Kevin J. Blinder (I); Bradley T. Smith (I); Ginny S. Nobel (C); Rhonda F. Weeks (C); Erika A. Hoehn (C); Maria A. Stuart (V); Kelly E. Pepple (V); Lynda K. Boyd (V); Brook G. Pulliam (V); Steve A Schremp (P); Stephanie L. Guevara (P); Jarrod Wehmeier (P); Timothy L Wright (P); Dana L Gabel (P); Beachwood, Ohio: Retina Associates of Cleveland Inc (10): David G. Miller (I); Jerome P. Schartman (I); Lawrence J. Singerman (I); Joseph M. Coney (I); Michael A. Novak (I); Llewelyn J. Rao (I); Susan C. Rath (C, V); Elizabeth McNamara (C, V); Larraine Stone (C); Veronica A. Smith (C); Cecelia Rykena (V); Kimberly A. DuBois (V); Mary A Ilc (V); Vivian Tanner (V); Kim Drury (V); Trina M. Nitzsche (P); Gregg A. Greanoff (P); John C. DuBois (P); Plantation, Florida: Fort Lauderdale Eye Institute (10): Stuart K. Burgess (I); Tirso M. Lara (I); Noel H. Pereda (C); Cindy V. Fernandez (C, V); Deborah Davis (V); Evelyn Quinchia (V); Karen Workman (P); West Des Moines, Iowa: Wolfe Eye Clinic (10): Jared S. Nielsen (I); Jeong-Hyeon Sohn (I); Kyle J. Alliman (I); David D. Saggau (I); Marianne Parker (C, V); Bethany George (C); Carrie L. Eastvold (C); Kristin Sells (C); Tami Jo Woehl (C); Marilyn A. Johnson (V); Holly Keenan (V); Jennifer L. Coleman (V); Jamie Spillman (V); Shannon Freeman (P); Leigh S Schmidt (P); Lisa M. Boender (P); Jill L. Partin (P); Bailey R. Bennett (P); Jay Rostvold (P); Asheville, North Carolina: Western Carolina Retinal Associates PA (9): Cameron McLure Stone (I); Lea R. Raymer (C); Andrea K. Menzel (C); Leslie D. Rickman (V); Barbara Campbell (V); Lorraine P. Sherlin (V); Lisa H. Hawkins (P); Melissa L. Buckner (P); Olesya N. Matsipura (P); Paula A. Price (P); Fort Myers, Florida: National Ophthalmic Research Institute (9): A. Thomas Ghuman (I); Paul A. Raskauskas (I); Ashish G. Sharma (I); Glenn Wing (I); Joseph P. Walker (I); Eileen Knips (C); Cheryl Kiesel (C); Crystal Y. Peters (C); Cheryl Ryan (C); Laura Greenhoe (C); Natalie N. Torres (C); Rebecca J Youngblood (C); Danielle Turnbo (V); Anita H. Leslie (V); Etienne C. Schoeman (P); Raymond K. Kiesel (P); Oklahoma City, Oklahoma: Dean A. McGee Eye Institute (9): Ronald M. Kingsley (I); Vinay A. Shah (I); Robert E. Leonard (I); Heather R. Miller (C); Sonny Icks (C); Vanessa A. Bergman (C, V); Vanessa K. Drummond (C); Brittany L Ross (C, V); Reshial D. Ellis (C); Tina R. Whittington (V); Shannon R. Almeida (V); Amanda M Butt (P); Russ Burris (P); Portland, Oregon: Retina Northwest PC (9): Mark A. Peters (I); Michael S. Lee (I); Paul S. Tlucek (I); Colin Ma (I); Stephen Hobbs (C, V); Amanda C. Milliron (C, V); Stephanie L. Ho (C, V); Marcia Kopfer (V); Joe Logan (P); Christine Hoerner (P); Houston, Texas: Retina and Vitreous of Texas (8): Joseph A. Khawly (I); Hassan T. Rahman (I); Diana Abdelgani (C); Pam S. Miller (C, V); Debbie Fredrickson (V); Erica Pineda (V); Desiree Lopez (P); Donald K. Lowd (P); Colin Blank (P); Lorena R. Martinez (P); Jason E. Muniz (P); Madison, Wisconsin: University of Wisconsin-Madison, Department of Ophthalmology/Retina Service (8): Justin Gottlieb (I); Michael S. Ip (I); Barbara A. Blodi (I); Kristine A. Dietzman (C, V); Kathryn F. Burke (C); Christopher M. Smith (C, V); Shelly R. Olson (V); Angela M. Wealti (V); Sandie L. Reed (P); Denise A. Krolnik (P); John C. Peterson (P); McAllen, Texas: Valley Retina Institute (8): Victor Hugo Gonzalez (I); Roberto Diaz-Rohena (I); Juan G. Santiago (I); Rohit Adyanthaya (I); Nehal R. Patel (I); Deyla Anaya (C); Dina Garcia (C); Edna E. Cruz (C); Crystal A. Alvarez (C); Ruth Iracheta (C); Jessica Rodriguez (C); Monica R. Cantu (V); Rebecca R. Flores (V); Hector Jasso (V); Rachel Rodriguez (V); Karina Miranda (V); Krystle R. Lozano (V); Maricela Garza (V); Lazaro Aguero (P); Amanda L. Sandoval (P); Monique Montemayor (P); Samuel Alonso (P); Santos Garza (P); Rochester, New York: University of Rochester (8): David Allen DiLoreto (I); Rajeev S. Ramchandran (I); David M. Kleinman (I); George W. O'Gara (C); Andrea M. Czubinski (C, V); Peter MacDowell (C); Kari M. Steinmetz (C); Dan A Castillo (V); Yvonne F. Yu (V); Salina M. Tongue (V); Melissa S Keim (V); Rachel Hollar (P); Brandi N. Deats (P); Brittany S. Richardson (P); Lynn Singer (P); Taylor A. Pannell (P); Walnut Creek, California: Bay Area Retina Associates (8): Stewart A. Daniels (I); Tushar M. Ranchod (I); Craig J. Leong (I); Stacey Touson (C, V); Shannon R. Earl (C); Melissa C. Bartlett (V); Christine Fernando (V); Djorella Factor (V); Jessica Garcia (V); Anna K. Nguyen (P); Betty Hom (P); Cathy Walker (P); Grace M. Marudo (P); Jose Carlos Suazo (P); Leah M. McNeil (P); Fred Hanamoto (P); Matthew D. Hughes (P); Grand Blanc, Michigan: Retina Vitreous Center (7): Robin D. Ross (I); Susan M. Sanford (C); Nicole Martini Markiewicz (C); Tracy M. Utley (C, V); Shannon Henderson (V); Joanie H. Lippincott (P); Patricia Streasick (P); Grand Rapids, Michigan: Vitreo-Retinal Associates (7): Louis C. Glazer (I); Frank W. Garber (I); Jeffrey D. Zheutlin (I); Angela D. Listerman (C, V); Christine E. Feehan (V); Heather L. Cruz (V); Donald E. Kuitula (P); Olivia P. Rainey (P); Sue Weatherbee (P); Knoxville, Tennessee: Southeastern Retina Associates PC (7): Joseph M. Googe (I); R. Keith Shuler (I); Nicholas G. Anderson (I); Stephen L. Perkins (I); Kristina Oliver (C); Nicole Grindall (V); Ann Arnold (V); Jennifer Beerbower (V); Cecile Hunt (V); Kathy L. Schulz (V); Sarah M. Oelrich (P); Jerry K. Whetstone (P); Justin Walsh (V); Chris Morris (P); Austin, Texas: Austin Retina Associates (6): Robert W. Wong (I); Peter A. Nixon (I); Jeni L. Leon (C); Chris A. Montesclaros (C); Carrie E. Leung (C); Phill Le (V); Codey L. Harborth (P); Margaret A. Rodriguez (P); Cory Mangham (P); Grand Rapids, Michigan: Retina Specialists of Michigan (6): Thomas M. Aaberg (I); Scott J. Westhouse (I); Holly L. Vincent (C, V); Rebecca Malone (V); Kathy L. Karsten (P); Indianapolis, Indiana: Raj K. Maturi, MD, PC (6): Raj K. Maturi (I); Ashley M. Harless (C, V); Carolee K. Novak (C, V); Laura A. Bleau (C, V); Thomas Steele (P); Charlotte Harris (P); Alisha Bildner (P); Abby Maple (P); Lexington, Kentucky: Retina and Vitreous Associates of Kentucky (6): Thomas W. Stone (I); Rick D. Isernhagen (I); John W. Kitchens (I); Diana M. Holcomb (C, V); Jeanne Van Arsdall (V); Michelle Buck (P); Edward A Slade (P); Albuquerque, New Mexico: Eye Associates of New Mexico (5): Mark T. Chiu (I); Ashok K. Reddy (I); Frank W. Wyant (I); Mary M. Montano-Niles (C); Lorraine J. Carter (C, V); Shirley Maerki (V); Laura Tartaglia (V); Paul P. Gomez (P); Stephen A. Maestas (P); Camille Shanta (P); Lisbrenda M. Jimenez (P); Atlanta, Georgia: Georgia Retina PC (5): Robert A. Stoltz (I); Stephanie L. Vanderveldt (I); Scott I. Lampert (I); Leslie G. Marcus (C); Shelly Fulbright (V); James P. Martin (P); Beverly Hills, California: Retina-Vitreous Associates Medical Group (5): Roger L. Novack (I); David S. Liao (I); Tammy Eileen Lo (C); Janet Kurokouchi (C); Richard Ngo (C); Connie V. Hoang (C); Julio Sierra (V); Adam Zamboni (V); Eric G. Protacio (P); Jeff Kessinger (P); Chapel Hill, North Carolina: University of North Carolina, Kittner Eye Center (5): Seema Garg (I); Odette M. Houghton (I); Jan Niklas Ulrich (I); Sai H. Chavala (I); Elizabeth L. DuBose (C, V); Cassandra J. Barnhart (C, V); Megha Karmalkar (C, V); Pooja D. Jani (V); Justin Goble (V); Debra Cantrell (P); Rona Lyn Esquejo (P); Edmond, Oklahoma: Retina Vitreous Center (5): Sandeep N. Shah (I); Natasha Harmon (C, V); Fort Lauderdale, Florida: Retina Group of Florida (5): Mandeep S. Dhalla (I); Mario R. del Cid (I); Lawrence S. Halperin (I); Jaclyn A. Brady (C); Monica Hamlin (C); Monica L. Lopez (C,P); Jamie Mariano (V); Candace M. Neale (P); Rita R. Veksler (P); Angelica Mannarelli (P); Houston, Texas: Baylor Eye Physicians and Surgeons (5): Robert E. Coffee (I); Petros Euthymiou Carvounis (I); Pejman Hemati (C, V); Cindy J. Dorenbach (C, V); Annika S. Joshi (C, V); April Leger (V); Dana B. Barnett (P); Joseph F. Morales (P); Leesburg, Virginia: Virginia Retina Center (5): Sam E. Mansour (I); Cathy Choyce (C, V); Aissa L. Dirawatun (V); Emma A. Nagy (V); Jamie C Kerkstra (P); Loma Linda, California: Loma Linda University Health Care, Department of Ophthalmology (5): Joseph T. Fan (I); Mukesh Bhogilal Suthar (I); Michael E. Rauser (I); Gisela Santiago (C, V); Liel Marvyn Cerdenio (C); Brandi J Perez (C, V); Kara E. Halsey (C, V); William H. Kiernan (V); Jesse Knabb (P); Rachel Catren (P); Lubbock, Texas: Texas Retina Associates (5): Michel Shami (I); Brenda K. Arrington (C, V); Keri S. Neuling (C); Ashaki Meeks (V); Natalie R. Garcia (V); Kayla Blair (P); Ginger K. Rhymes (P); Janet Medrano (P); Milwaukee, Wisconsin: Medical College of Wisconsin (5): Judy E. Kim (I); David V. Weinberg (I); Kimberly E. Stepien (I); Thomas B. Connor (I); Vesper V. Williams (C); Tracy L. Kaczanowski (C); Krissa L. Packard (C); Judy Flanders (V); Vicki Barwick (V); Pat A. Winter (V); Joseph R. Beringer (P); Kathy J. Selchert (P); Orlando, Florida: Magruder Eye Institute (5): John T. Lehr (I); Elaine Rodriguez-Roman (C); Teri Jones (V); Martha Eileen Haddox (V); Mark Pena (P); Brenda Hernandez (P); Palm Desert, California: Southern California Desert Retina Consultants, MC (5): Clement K. Chan (I); Maziar Lalezary (I); Steven G Lin (I); Kimberly S. Walther (C); Tiana Gonzales (C); Lenise E. Myers (V); Kenneth M. Huff (P); Portsmouth, New Hampshire: Eyesight Ophthalmic Services PA (5): Richard Chace (I); Sunny Kallay (C); Kirsten Stevens (V); Nicole Dolbec (V); Ronda Baker-Hill (V); Janea Surette (P); Rochester, New York: Retina Associates of Western New York (5): Steven J. Rose (I); Brian P. Connolly (I); Ernest G. Guillet (I); Edward F. Hall (I); Margaret M. Yagoda (C); Mary Jo Doran (C); Mindy Burgess (V); Ann Reynard (V); Margaret Powers (P); Joe Territo (P); San Antonio, Texas: Retinal Consultants of San Antonio (5): Calvin E. Mein (I); Moises A. Chica (I); R. Gary Lane (I); Sarah Elizabeth Holy (I); Lita Kirschbaum (C, V); Vanessa D Martinez (C); Jaynee Baker (C); Christa G. Kincaid (V); Elaine Castillo (P); Christopher Sean Wienecke (P); Sara L. Schlichting (P); Brenda Nakoski (P); Westlake Village, California: Retinal Consultants of Southern California Medical Group, Inc. (5): Kenneth R. Diddie (I); Deborah M. Cadwell (C); Louise Van Arsdale (V); Taryn F. Boisvert (P); Joyce Galonsky (P); Susie O'Hayer (P); Melissa L. Johnson (P); Worcester, Massachusetts: Vitreo-Retinal Associates PC (5): Frank J. McCabe (I); Brad J. Baker (I); Melvyn H. Defrin (I); Marie V. Lampson (C); Heather Pratte (V); Selena A. Baron (V); Aundrea S. Borelli (V); Columbus, Ohio: OSU Eye Physicians and Surgeons LLC. (4): Frederick H. Davidorf (I); Michael B. Wells (I); Susie Chang (I); John Byron Christoforidis (I); Alan D. Letson (I); Jill A Salerno (C); Jerilyn G. Perry (V); Stephen E. Shelley (P); Patrick J. Fish (P); Dubuque, Iowa: Medical Associates Clinic PC (4): Michael H. Scott (I); James A. Dixon (I); Shannon R. Walsh (C); Philomina M. Ozpirincci (C); Brenda L. Tebon (P); Marcia J. Moyle (P); Lancaster, Pennsylvania: Family Eye Group (4): Michael R. Pavlica (I); Noelle S Matta (C, V); Cristina M. Brubaker (P); Alyson B. Backer (P); Newark, New Jersey: The Institute of Ophthalmology and Visual Science (IOVS) (4): Neelakshi Bhagat (I); Catherine Fay (C, V); Tatiana Mikheyeva (P); Michael Lazar (P); Janie D. Ellenberger (P); Beth Malpica (P); Philadelphia, Pennsylvania: University of Pennsylvania Scheie Eye Institute (4): Alexander J. Brucker (I); Benjamin J. Kim (I); Brian L. VanderBeek (I); Sheri Drossner (C, V); Joan C. DuPont (C, V); Rebecca Salvo (C); Stephanie B. Engelhard (C); Jim M. Berger (P); Sara Morales (P); Beth Serpentine (P) ;Sandy Springs, Georgia: Thomas Eye Group (4): Paul L. Kaufman (I); Jessica D. McCluskey (I); Kathy T. Wynne (C, V); Julian Jordan (P); Brandun Watson (P); Spokane, Washington: Spokane Eye Clinic (4): Robert S. Wirthlin (I); Eric S. Guglielmo (I); Eileen A. Dittman (C, V); Dylan C. Waidelich (C, V); Cristofer J. Garza (P); Adeline M. Stone (P); Ashley Nicole Oakes (P); Tampa, Florida: Retina Associates of Florida, P.A. (4): Ivan J. Suner (I); Mark E. Hammer (I); Marc C. Peden (I); Janet R. Traynom (C); Rochelle DenBoer (C); Heidi Vargo (V); Susan Ramsey (V); Anita Kim Malzahn (P); Debra Jeffres (P); Trumbull, Connecticut: New England Retina Associates, PC (4): Nauman A. Chaudhry (I); Sumit P. Shah (I); Gregory M. Haffner (I); Emiliya German (C); Shannan Moreau (C); Laura A. Fox (C, V); Jennifer M. Matteson (C); JoAnna L. Pelletier (C); Alison Fontecchio (V); Emily Morse (P); Greg McNamara (P); Marie Grace Laglivia (P); Marissa L. Scherf (P); Angela LaPre (P); Justin A. Cocilo (P); Albuquerque, New Mexico: University of New Mexico Health Sciences Center (3): Arup Das (I); Linda Friesen (C); Michele Franco (V); Johnny Lucero (V); Melissa Frazier (V); Robert Laviolette (P); Bronx, New York: Montefiore Medical Center (3): Umar Khalil Mian (I); Rebecca L. Riemer (C); Evelyn Koestenblatt (C); Louise V. Wolf (C); Christine Kim (V); Irina Katkovskaya (V); Erica Otoo (V); Kevin A. Ellerbe (P); Kenneth Boyd (P); Caroline Costa (P); Detroit, Michigan: Henry Ford Health System, Department of Ophthalmology and Eye Care Services (3): Paul Andrew Edwards (I); Hua Gao (I); Thomas Hessburg (I); Uday Desai (I); Janet Murphy (C, V); Mary K. Monk (C, V); Julianne Hall (C, V); Melina Mazurek (C, V); Katie M. Ventimiglia (C, V); Brian A. Rusinek (P); Bradley A. Stern (P); Kris Brouhard (P); Katie M. Weier (P); Megan Allis (P); Jenny Shaken (P); Nicole M. Massu (P); Tracy A. Troszak (P); David Burley (P); Minneapolis, Minnesota: Retina Center, PA (3): Abdhish R. Bhavsar (I); Geoffrey G. Emerson (I); Jacob M. Jones (I); Tracy A. Anderson (C, P); Andrea Gilchrist (C); Matt D. Peloquin (C, P, V); Gaid Gaid (V); Yang Vang (V); Samantha Ryan (P); Denise Vang (P); Alanna C. Evans (P); Tonja Scherer (P); New Albany, Indiana: John-Kenyon American Eye Institute (3): Howard S. Lazarus (I); Debra Paige Bunch (C, V); Liana C. Davis (C, V); Kelly Booth (V); Margaret Trimble (P); Mary A. Bledsaw (P); Jay Moore (P); New York, New York: Macula Care (3): Daniel F. Rosberger (I); Sandra Groeschel (C); Miriam A. Madry (C); Nikoletta DiGirolamo (C); Dustin Pressley (V); Robert Santora (P); Yenelda M. Gomez (V); Pittsburgh, Pennsylvania: Retina Vitreous Consultants (3): Karl R. Olsen (I); Robert L. Bergren (I); P. William Conrad (I); Pamela P. Rath (I); Avni Patel Vyas (I); Judy C Liu (I); Lori A. Merlotti (C); Jennifer L. Chamberlin (C); Holly M. Mechling (C); Mary E. Kelly (C); Kellianne Marfisi (V); Kimberly A. Yeckel (V); Veronica L. Bennett (V); Christina M. Schultz (V); Grace A. Rigoni (V); Julie Walter (V); Missy A. Forish (V); Amanda Fec (P); Courtney L. Foreman (P); David Steinberg (P); Keith D McBroom (P); Sarasota, Florida: Sarasota Retina Institute (3): Melvin C. Chen (I); Marc H. Levy (I); Waldemar Torres (I); Peggy Jelemensky (C); Tara L. Raphael (V); Joann Rich (V); Mark Sneath (P); Seattle, Washington: University of Washington Medical Center (3): James L. Kinyoun (I); Gurunadh Atmaram Vemulakonda (I); Susan A. Rath (C, V); Patricia K. Ernst (C, V); Juli A. Pettingill (V); Ronald C. Jones (P); Brad C. Clifton (P); James D. Leslie (P); Baltimore, Maryland: Wilmer Eye Institute at Johns Hopkins (2): Sharon D. Solomon (I); Neil M. Bressler (I); Lisa K. Levin (C); Deborah Donohue (C, V); Mary Frey (C, V); Lorena Larez (V); Keisha Murray (V); Rita L. Denbow (V); Janis Graul (P); David Emmert (P); Charles Herring (P); Nick Rhoton (P); Joe Belz (P); Chicago, Illinois: Northwestern Medical Faculty Foundation (2): Alice T. Lyon (I); Rukhsana G. Mirza (I); Amanda M. Krug (C, V); Carmen Ramirez (C, V); Lori Kaminski (C); Anna Liza M. Castro-Malek (C, V); Amber N. Mills (V); Zuzanna Rozenbajgier (V); Marriner L. Skelly (P); Evica Simjanoski (P); Andrea R. Degillio (P); Chicago, Illinois: University of Illinois at Chicago Medical Center (2): Jennifer I. Lim (I); Felix Y. Chau (I); Marcia Niec (C); Tametha Johnson (V); Yesenia Ovando (V); Mark Janowicz (P); Catherine Carroll (P); Columbia, South Carolina: Carolina Retina Center (2): Jeffrey G. Gross (I); Barron C. Fishburne (I); Amy M. Flowers (C, V); Riley Stroman (C, V); Christen Ochieng (C, V); Angelique SA McDowell (V); Ally M. Paul (P); Randall L. Price (P); Honolulu, Hawaii: Retina Associates of Hawaii, Inc. (2): John H. Drouilhet (I); Erica N. Lacaden (C); Deborah J. Nobler (C, V); Kingsport, Tennessee: Southeastern Retina Associates, PC (2): Howard L. Cummings (I); Deanna Jo Long (C, V); Ben McCord (V); Jason Robinson (V); Jamie Swift (P); Julie P. Maynard (P); New York, New York: Mount Sinai School of Medicine, Department of Ophthalmology (2): Patricia J. Pahk (I); Hannah Palmer-Dwore (C); Dipali H. Dave (C, V); Mariebelle Pacheco (V); Barbara A. Galati (P); Eneil Simpson (P); Rochester, Minnesota: Mayo Clinic Department of Ophthalmology (2): Andrew J. Barkmeier (I); Diane L. Vogen (C); Karin A. Berg (V); Shannon L. Howard (V); Jean M. Burrington (V); Jessica Ann Morgan (V); Joan T. Overend (V); Shannon Goddard (P); Denise M. Lewison (P); Jaime L. Tesmer (P); Winston-Salem, North Carolina: Wake Forest University Eye Center (2): Craig Michael Greven (I); Joan Fish (C, V); Cara Everhart (C, V); Mark D. Clark (P); David T Miller (P); Atlanta, Georgia: Emory Eye Center (1) Andrew M. Hendrick (I); George Baker Hubbard (I); Jiong Yan (I); Blaine E. Cribbs (I); Linda T. Curtis (C, V); Judy L. Brower (V); Jannah L. Dobbs (P); Debora J. Jordan (P); Cleveland, Ohio: Case Western Reserve University (1): Baseer U. Ahmad (I); Suber S. Huang (I); Hillary M. Sedlacek (C); Cherie L. Hornsby (C); Lisa P. Ferguson (C); Kathy Carlton (V); Kelly A. Sholtis (V); Peggy Allchin (V); Claudia Clow (V); Mark A. Harrod (P); Geoffrey Pankhurst (P); Irit Baum-Rawraway (P); Stacie A. Hrvatin (P); New York, New York: The New York Eye and Ear Infirmary/Faculty Eye Practice (1): Ronald C. Gentile (I); Alex Yang (C, V); Wanda Carrasquillo-Boyd (P); Robert Masini (P); Ocala, Florida: Ocala Eye Retina Consultants (1): Chander N. Samy (I); Robert J. Kraut (I); Kathy Shirley (C); Linsey Corso (C); Karen Ely (V); Elizabeth Scala (P); Stewart Gross (P); Vanessa Alava (P); Omaha, Nebraska: University of Nebraska Medical Center, Department of Ophthalmology (1): Eyal Margalit (I); Donna G. Neely (C); Maria Blaiotta (V); Lori Hagensen (P); Tucson, Arizona: Retina Associates (1): April E. Harris (I); Rita L. Lennon (C); Denice R. Cota (V); Larry Wilson (P). Protocol Development Committee: John A. Wells, III, Lloyd P. Aiello, Roy W. Beck, Neil M. Bressler, Susan B. Bressler, Kakarla V. Chalam, Ronald P. Danis, Bambi J. Arnold-Bush, Frederick Ferris, Scott M. Friedman, Adam R. Glassman, Michael H. Scott, Jennifer K. Sun, Robert W. Wong.

Disclaimer: Dr Bressler is the Editor of JAMA Ophthalmology. He was not involved in the editorial evaluation or decision to accept this article for publication.

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