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Figure 1.
Two-Way Sensitivity Analysis Verifying Cost of Anti–Vascular Endothelial Growth Factor (VEGF) and Cost of Panretinal Photocoagulation (PRP) for Persons With and Without Vision-Impairing Diabetic Macular Edema (DME) at Baseline
Two-Way Sensitivity Analysis Verifying Cost of Anti–Vascular Endothelial Growth Factor (VEGF) and Cost of Panretinal Photocoagulation (PRP) for Persons With and Without Vision-Impairing Diabetic Macular Edema (DME) at Baseline

Colors represent the incremental cost-effectiveness ratios. Although there are no official thresholds of cost-effectiveness in the United States, generally, interventions costing less than $50 000 to $150 000 would be considered cost-effective.18

ICER indicates incremental cost-effectiveness ratios.

Figure 2.
Cost-effectiveness Acceptability Curve
Cost-effectiveness Acceptability Curve

Lines represent the probability ranibizumab was cost-effective (y-axis) at willingness-to-pay for quality-adjusted life-year (QALY) gains (x-axis).

Table 1.  
Mean per-Patient Costs of Ranibizumab and Panretinal Photocoagulation Groups Over 2 Years of Follow-up (in 2016 US Dollars)
Mean per-Patient Costs of Ranibizumab and Panretinal Photocoagulation Groups Over 2 Years of Follow-up (in 2016 US Dollars)
Table 2.  
Change in Quality-Adjusted Life-years and Cost-effectiveness Results During 2 Years (Utilities Converted From Visual Acuity in the Better-Seeing Eye)
Change in Quality-Adjusted Life-years and Cost-effectiveness Results During 2 Years (Utilities Converted From Visual Acuity in the Better-Seeing Eye)
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Gross  JG, Glassman  AR, Jampol  LM,  et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network.  Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.  JAMA. 2015;314(20):2137-2146.PubMedGoogle ScholarCrossref
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Owsley  C, McGwin  G  Jr, Scilley  K, Kallies  K.  Development of a questionnaire to assess vision problems under low luminance in age-related maculopathy.  Invest Ophthalmol Vis Sci. 2006;47(2):528-535.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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Czoski-Murray  C, Carlton  J, Brazier  J, Young  T, Papo  NL, Kang  HK.  Valuing condition-specific health states using simulation contact lenses.  Value Health. 2009;12(5):793-799.PubMedGoogle ScholarCrossref
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Briggs  A, Fenn  P.  Confidence intervals or surfaces? uncertainty on the cost-effectiveness plane.  Health Econ. 1998;7(8):723-740.PubMedGoogle ScholarCrossref
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Lin  J, Chang  JS, Smiddy  WE.  Cost evaluation of panretinal photocoagulation versus intravitreal ranibizumab for proliferative diabetic retinopathy.  Ophthalmology. 2016;123(9):1912-1918.PubMedGoogle ScholarCrossref
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The Diabetic Retinopathy Study Research Group.  Preliminary report on effects of photocoagulation therapy.  Am J Ophthalmol. 1976;81(4):383-396.PubMedGoogle ScholarCrossref
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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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Elman  MJ, Aiello  LP, Beck  RW,  et al; Diabetic Retinopathy Clinical Research Network.  Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;117(6):1064-1077.e35.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
Original Investigation
June 2017

Cost-effectiveness of Intravitreous Ranibizumab Compared With Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Secondary Analysis From a Diabetic Retinopathy Clinical Research Network Randomized Clinical Trial

Author Affiliations
  • 1Department of Health Management and Policy, University of Michigan School of Public Health, Ann Arbor
  • 2Department of Industrial and Operations Engineering, University of Michigan College of Engineering, Ann Arbor
  • 3Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor
  • 4Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor
  • 5Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 6Editor, JAMA Ophthalmology
  • 7Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 8Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, North Carolina
  • 9Jaeb Center for Health Research, Tampa, Florida
JAMA Ophthalmol. 2017;135(6):576-584. doi:10.1001/jamaophthalmol.2017.0837
Key Points

Question  What are the incremental cost-effectiveness ratios of 0.5-mg ranibizumab therapy to panretinal photocoagulation for proliferative diabetic retinopathy?

Findings  This preplanned secondary analysis of a randomized clinical trial found that for participants with and without baseline vision-impairing diabetic macular edema, the incremental cost-effectiveness ratios of ranibizumab therapy compared with panretinal photocoagulation were $55 568/quality-adjusted life-year and $662 978/quality-adjusted life-year, respectively, over 2 years.

Meaning  Compared with panretinal photocoagulation, 0.5-mg ranibizumab was cost-effective for eyes presenting with proliferative diabetic retinopathy and vision-impairing diabetic macular edema but not for those with proliferative diabetic retinopathy without vision-impairing diabetic macular edema.

Abstract

Importance  The Diabetic Retinopathy Clinical Research Network Protocol S randomized clinical trial results suggest that ranibizumab is a reasonable treatment alternative to panretinal photocoagulation (PRP) when managing proliferative diabetic retinopathy (PDR), with or without concomitant baseline diabetic macular edema (DME). However, ranibizumab injections are costly. Thus, it would be useful to examine the relative cost-effectiveness of these 2 treatment modalities.

Objective  To evaluate incremental cost-effectiveness ratios of 0.5-mg ranibizumab therapy vs PRP for PDR.

Design, Setting, and Participants  Preplanned secondary analysis using efficacy, safety, and resource utilization data through 2 years of follow-up at 55 US sites for 213 adults with PDR. Data were collected from February 2012 to January 2015.

Interventions  Intravitreous 0.5-mg ranibizumab at baseline and as frequently as every 4 weeks based on a structured retreatment protocol or PRP at baseline for PDR. Eyes in both groups could receive ranibizumab for concomitant DME.

Main Outcomes and Measures  Incremental cost-effectiveness ratios of ranibizumab compared with PRP evaluated within 2 prespecified subgroups for the study eye: with baseline vision-impairing (Snellen equivalent 20/32 or worse) DME and without baseline vision-impairing DME.

Results  The study included 305 adults with PDR, the mean age was 52 years, 44% were women, and 52% were white. Of the 46 participants with PDR and vision-impairing DME at baseline, 21 were assigned to the ranibizumab group and 25 to the PRP group (plus ranibizumab for DME). Among the remaining participants without baseline vision-impairing DME, 80 and 87 were in the ranibizumab and PRP groups, respectively. For participants with and without baseline vision-impairing DME, the incremental cost-effectiveness ratios of ranibizumab therapy compared with PRP were $55 568/quality-adjusted life-year and $662 978/quality-adjusted life-year, respectively, over 2 years.

Conclusions and Relevance  Over 2 years, compared with PRP, 0.5-mg ranibizumab as given in this trial is within the $50 000/quality-adjusted life-year to $150 000/quality-adjusted life-year range frequently cited as cost-effective in the United States for eyes presenting with PDR and vision-impairing DME, but not for those with PDR without vision-impairing DME.

Trial Registration  Clinicaltrials.gov Identifier: NCT01489189.

Introduction

Diabetic retinopathy is the most common cause of blindness among working-age adults.1,2 Many patients have nonproliferative diabetic retinopathy; however, some develop proliferative diabetic retinopathy (PDR), which can lead to blindness from traction retinal detachment, vitreous hemorrhage, or neovascular glaucoma. Panretinal photocoagulation (PRP) has been the standard care for treating most eyes with PDR for decades but destroys retinal tissue, which may cause iatrogenic peripheral vision loss or exacerbation of diabetic macular edema (DME), resulting in central vision loss. The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S randomized clinical trial comparing intravitreous antivascular endothelial growth factor (anti-VEGF) therapy using 0.5-mg ranibizumab vs PRP for patients with PDR demonstrated that eyes in the ranibizumab group had a mean visual acuity change from baseline to 2 years that was noninferior to PRP.3 In addition, the ranibizumab group had better outcomes across a variety of dimensions, including better visual acuity change from baseline over 2 years (area under the curve), less peripheral visual field sensitivity loss, fewer vitrectomies for complications of PDR, and fewer eyes developing DME with vision loss among eyes without DME at baseline. Eyes in both groups could receive ranibizumab for treatment of DME.

However, ranibizumab therapy is much more expensive than PRP treatment. Each single-use vial of 0.5-mg ranibizumab costs $1916 plus a $103 procedural or surgical fee for administering the injection.4 By comparison, each PRP treatment costs $345.4 Because patients often require multiple injections, the cost differential between the 2 treatment options can be substantial. Thus, while ranibizumab may be a viable alternative therapy to PRP for clinical outcomes, questions remain as to which is more cost-effective. This study reports a preplanned secondary analysis from the DRCR.net Protocol S assessing incremental cost-effectiveness of 0.5-mg ranibizumab vs PRP for the treatment of PDR.

Methods
Overview

In a DRCR.net randomized clinical trial at 55 clinical sites throughout the United States from February 2012 to January 2015, trial participants were at least 18 years old, had type 1 or 2 diabetes, had PDR in at least 1 eye, no prior PRP, no intraocular anti-VEGF therapy in the prior 2 months, and a best-corrected visual acuity letter score of at least 24 (approximate Snellen equivalent of 20/320 or better). If both eyes were eligible, participants could have 2 eyes in the study, 1 eye treated with PRP and 1 with ranibizumab. However, because it is not possible to partition cost-effectiveness of each treatment when both eyes received different treatments, this analysis only evaluates the 213 participants (70% of study participants) with 1 study eye. The study adhered to the tenets of the Declaration of Helsinki and was approved by local institutional review boards or a central institutional review board if the site did not have a local board. Study participants provided written informed consent.

Eyes assigned to ranibizumab injections for PDR were treated as often as monthly based on specific retreatment criteria.3 These eyes also could receive PRP if protocol-defined failure criteria were met. Eyes assigned to PRP for PDR received PRP at baseline and then again during follow-up if the size or extent of neovascularization increased. Eyes in both groups were required to receive 0.5-mg ranibizumab for vision-impairing central-involved DME (visual acuity letter score ≤78 [approximate Snellen equivalent 20/32 or worse]) at baseline and could receive ranibizumab injections to treat DME if needed during the course of the trial. Because eyes with vision-impairing DME at baseline were required to initiate ranibizumab therapy for DME at entry in both treatment groups, the cost-effectiveness analysis of the 2 interventions was performed within subgroups for persons with and without vision-impairing DME at baseline. Additional details on the study protocols and eligibility can be found in the publication on the primary outcome.3

Analysis Plan

All eyes had best-corrected visual acuity measurements obtained at baseline and every 16 weeks. The protocol planned an economic analysis and specified collection of data on cost and health-related quality of life, enabling a cost-utility analysis to be performed. During the trial, resource utilization data were collected, including number of clinic visits and number and types of diagnostic and therapeutic ocular procedures performed in each group. The study also collected functional outcome data related to vision at baseline and annually.5-7 Other outcomes included patient-level health preferences using a time-tradeoff questionnaire.8A P value of < .05 was considered significant, and P values are 2-sided.

Costs

To capture patient resource utilization during the trial, cost data for all diagnostic/therapeutic ocular procedures performed were tabulated to obtain a total cost for eye care services during 2 years of follow-up. Costs were calculated based on the 2016 Medicare fee schedule of allowable charges and included physician and facility fees.4 In addition, costs associated with treatment of ocular (eg, vitrectomy for complications of PDR or endophthalmitis) and systemic adverse events (eg, myocardial infarction and cerebrovascular accident) that potentially may be associated with treatment during the trial were computed. A detailed listing of costs can be found in eTables 1 and 2 in the Supplement.

Health Utility

To capture changes in health-related quality of life associated with receipt of the 2 interventions over the course of the trial, best-corrected visual acuities at the 16-week, 32-week, 52-week, 68-week, 84-week, and 104-week visit from the better-seeing eye were converted into quality-adjusted life-years (QALYs) using commonly used mappings by Brown et al.9 Prior research has shown that quality of life is most closely related to vision in the better-seeing eye.10 However, 3 other methods were used in the sensitivity analysis: 1 using the treated eye,11 1 using a utility scale with an upper anchor of perfect health instead of perfect vision, and 1 using patient time-tradeoff questions. More details can be found in the eAppendix in the Supplement.12

Cost-effectiveness

The incremental cost-effectiveness ratio (ICER) was calculated by taking the incremental cost of ranibizumab vs PRP and dividing by incremental QALYs gained of ranibizumab vs PRP. Incremental cost-effectiveness ratios were computed for subgroups with and without concomitant baseline DME. A higher ICER indicates a given intervention is less cost-effective than another.

Ten thousand bootstrap replications of the incremental effects and costs were created by sampling patients as well as sampling unit cost and visual acuity-to-utility data from distributions shown in eTable 1 in the Supplement. This nonparametric bootstrap creates incremental cost and QALY pairs used to create the cost-effectiveness acceptability curves that characterize overall uncertainty in the cost-effectiveness ratio.13

Results

Baseline characteristics of the study population for the cost-effectiveness analysis stratified by whether the eye was randomly assigned to receive PRP or ranibizumab and whether it had vision-impairing DME at baseline are shown in eTable 3 in the Supplement.

Costs

Participants in the PRP group receiving ranibizumab for vision-impairing DME at baseline received a mean of 7 ranibizumab injections during 2 years compared with 12 in the ranibizumab group with baseline DME. Over the 2-year study period, those with vision-impairing DME at baseline (Table 1) assigned to ranibizumab incurred costs of $29 574 compared with $24 520 for the PRP plus ranibizumab group (difference, $5053; 95% CI, −$7695 to $17 801). Those with PDR without vision-impairing DME at baseline assigned to ranibizumab incurred costs of $22 576 compared with $7445 for those given PRP, (difference, $15 131; 95% CI, $11 480 to −$18 782).

Health Utilities

When calculating health utilities based on best-corrected visual acuities in the better-seeing eye, ranibizumab showed a slight improvement vs PRP over 2 years. Table 2 shows participants with baseline vision-impairing DME had improvement in QALYs with ranibizumab relative to PRP (0.031 vs −0.06); the difference between the therapies was 0.091 (95% CI, −0.079 to 0.261). For eyes without baseline vision-impairing DME, ranibizumab had a QALY of −0.007 compared with −0.03 QALY for eyes treated with PRP (difference, 0.023; 95% CI, −0.037 to 0.82). Differences in health utilities using other methods (eg, using visual acuities from the treated eye or using questionnaire data) are in eTables 4-6 in the Supplement.

Cost-effectiveness

For patients with PDR and vision-impairing DME at baseline, the ICER of ranibizumab compared with PRP during a 2-year horizon was $55 568/QALY. Among patients with PDR and no vision-impairing DME at baseline, the ICER was $662 978/QALY (Table 2). Results using alternative methods for evaluating utilities show that if best-corrected visual acuity in the study eye was used as a surrogate for health-related quality of life (rather than best-corrected vision in the better-seeing eye), the ICER of the ranibizumab group vs the PRP group was almost $200 000/QALY and more than $500 000/QALY for those with and without vision-impairing DME, respectively (eTable 7 in the Supplement). The directly elicited utilities were highly variable for patients in both treatment groups, partially owing to refusals to answer the time-tradeoff utility questions, further reducing statistical power on an already highly variable measure (details in the eAppendix in the Supplement). Therefore, calculating the ICER of ranibizumab vs PRP using this approach was not done. eTable 8 in the Supplement shows that varying the costs of the procedures performed based on their highest and lowest reimbursable values had minimal effect on the ICER.

Sensitivity Analyses

A 1-way sensitivity analysis (varying 1 parameter and keeping all other inputs the same) shows the largest driver of cost-effectiveness is the cost of the anti-VEGF agent (eTable 9 in the Supplement). If the cost of ranibizumab were to drop to $900 per dose, then use of the anti-VEGF therapy without PRP for patients with PDR and vision-impairing DME at baseline would be considered cost-saving (improve quality of life and cost less) compared with treatment using ranibizumab for DME along with PRP for PDR (Figure 1A and eTable 9 in the Supplement). In a 2-way sensitivity analysis (where all model inputs were kept the same except for 2 parameters varied), if the cost of ranibizumab dropped to $400 per dose and the cost of PRP rose to $600 per laser session, then the use of anti-VEGF therapy for patients with PDR and no vision-impairing DME at baseline would be about $100 000/QALY (Figure 1B and eTable 10 in the Supplement).

The cost-effectiveness acceptability curves show uncertainty in all parameters simultaneously. Among participants with vision-impairing DME at baseline, the ranibizumab group would be more likely to be considered cost-effective than PRP if a decision maker was willing to spend more than $60 000/QALY. However, for patients without baseline vision-impairing DME, PRP is more likely to be considered cost-effective unless the decision maker was willing to spend $700 000/QALY or more (Figure 2).

Discussion

This preplanned secondary analysis suggests that for patients with PDR without baseline vision-impairing DME, PRP is more cost-effective than ranibizumab treatment through the 2-year follow-up visit. However, ranibizumab alone may be a more cost-effective therapeutic option through at least 2 years for patients with PDR who also have concomitant vision-impairing DME at baseline compared with using PRP to treat PDR and ranibizumab to treat DME as given in this trial. These findings need to be considered in the context of the clinically relevant benefits of ranibizumab compared with PRP reported after 2 years of follow-up in this trial. These benefits included that the group assigned to ranibizumab without PRP for PDR had better visual acuity through 2 years, less peripheral visual field loss, required fewer vitrectomies, and, among eyes without vision-impairing DME at baseline, were less likely to develop DME with vision impairment. While ongoing follow-up of these study participants continues, outcomes beyond 2 years were not simulated in this cost-effectiveness analysis because to our knowledge, there are no data in the literature to provide a reasonable approximation of future visual acuity outcomes, frequency of adverse events including vitrectomies, number of treatments, and costs beyond 2 years for participants in each of the treatment arms. If the number of injections tapers off but vision gains persist, the longer-term cost-effectiveness may improve.

While the costs of 1 or 2 PRP treatments are less expensive than ranibizumab given 10 to 13 times over 2 years, it is important to compare the complexity of true costs with the complexity of gains in quality of life for the ranibizumab and PRP group as analyzed in this cost-effectiveness analysis. This DRCR.net cost-effectiveness analysis is substantially different from the methods used in a prior article3,14 discussing costs of PRP vs ranibizumab using previously published data from the DRCR.net Protocol S but not from the DRCR.net investigators.3,14 That article reported that intravitreous ranibizumab compared with no therapy would have an ICER of $19 150 over 2 years. Many differences exist between that analysis and the one presented here. The other analysis used data from the Diabetic Retinopathy Study (from the 1970s) to model outcomes for eyes receiving PRP and assumed ranibizumab outcomes would be equivalent to PRP outcomes,12,15 whereas our DRCR.net cost-effectiveness analysis used actual visual acuities along with other efficacy and safety outcomes from Protocol S. Our DRCR.net analysis also considered actual resource utilization from trial participants. Furthermore, our DRCR.net study directly compared cost-effectiveness of ranibizumab vs PRP as opposed to comparing each therapy vs a strategy of no treatment. Nowadays, observation of high-risk PDR would be considered unethical for most patients. In addition, our DRCR.net study examined the clinically relevant subpopulations of patients with vision-impairing DME at baseline vs those without baseline DME, demonstrating ranibizumab was cost-effective for patients with vision-impairing DME at baseline and not as cost-effective as PRP for patients without vision-impairing DME at baseline, justifying the need for a stratified analysis. Our DRCR.net analysis also performed a 2-way sensitivity analysis, simultaneously varying the costs of anti-VEGF and PRP, allowing readers to apply the study findings to other anti-VEGF agents (if one were to assume those agents have equivalent efficacy and safety profiles as 0.5-mg ranibizumab) and to different prices for these interventions in other countries.

Limitations

Nevertheless, there are several limitations to our DRCR.net analysis. First, the use of best-corrected visual acuity in the better-seeing eye or the study eye as a surrogate for overall health-related quality of life may not fully capture all aspects of quality of well-being associated with receipt of these interventions. A sensitivity analysis using patient-elicited utility scores rather than visual acuity levels to capture health-related quality of life was attempted; however, those measurements were highly variable and fraught with missing data, so they could not be incorporated into these analyses. Second, only direct medical costs of select events were captured. Other costs, such as costs associated with caregiver burden, transportation costs to visits, and costs associated with time away from work, were not considered. Third, this analysis only used a 2-year time horizon because, to our knowledge, there are no studies with longer follow-up periods to provide confident estimates on the resource use, adverse effects, and costs beyond 2 years. Fourth, the original Protocol S trial did not dictate the exact retreatment algorithm when using ranibizumab to treat DME for those participants who had DME requiring anti-VEGF therapy during the course of 2 years. Therefore, it is possible that differences in how participating physicians opted to treat the DME may have added additional variability to the results. It is not possible to know what the costs or QALYs would be if a strict regimen to treat vision-impairing DME, as was required by protocol in other DRCR.net studies for DME treatment,16,17 was performed in this study. Fifth, this analysis did not attempt to quantify the health-related quality of life associated with peripheral visual field loss from PRP, which was substantially greater than the loss seen among eyes in the ranibizumab group and can have substantial effects on patients’ quality of life. Sixth, diabetes often affects both eyes, but because of the design of this study, we caution the application of these results to patients with bilateral DME. Additional research is needed to assess this group. Finally, because this trial only examined 0.5-mg ranibizumab, these data do not provide cost-effectiveness estimates of other anti-VEGF agents that may be used in clinical practice such as aflibercept, bevacizumab, or 0.3-mg ranibizumab. While the costs of these agents are known, other costs and the QALYs cannot be computed because the visual acuity and other ocular outcomes, such as number of injections, rates of vitrectomy, or development of vision-impairing DME in the absence of such DME at baseline, when using the other agents, may differ compared with the findings in the DRCR.net trial that used 0.5-mg ranibizumab. The 2-way sensitivity analysis does provide information about the potential ICERs of these other anti-VEGF agents vs PRP if one assumes equivalent efficacy, safety, and resource use, as was noted when 0.5-mg ranibizumab was used in Protocol S.

Conclusions

Compared with PRP over 2 years, 0.5-mg ranibizumab as given in this trial is within the $50 000/QALY to $150 000/QALY range frequently cited as cost-effective in the United States for eyes presenting with PDR and vision-impairing DME but not for those without baseline vision-impairing DME. From a societal perspective, in developed countries such as the United States, ranibizumab through 2 years as an alternative therapy to PRP for PDR with vision-impairing DME at baseline provides clinically relevant benefits and also is cost-effective. However, for PDR without vision-impairing DME, which may be the more common clinical presentation, PRP is the more cost-effective treatment option through at least 2 years. These results should be tempered by the small numbers of eyes evaluated, especially for the subgroups with PDR and vision-impairing DME at baseline. The cost-effectiveness acceptability curves (Figure 2) highlight uncertainty related to the small numbers. Furthermore, the lack of cost-effectiveness among eyes without vision-impairing DME at baseline is at odds with the potential benefits of anti-VEGF therapy in this situation, including better visual acuity over 2 years, less peripheral visual field loss, fewer vitrectomies, and fewer eyes developing vision-impairing DME (among eyes without vision-impairing DME at baseline) for which anti-VEGF therapy subsequently would be considered. Additional data beyond 2 years would be valuable to determine whether the cost-effectiveness results obtained at 2 years persist with longer follow-up. Until then, considerations of visual acuity and other ocular outcomes (such as visual field loss, need for vitrectomy, and need for anti-VEGF therapy for DME among eyes without DME at the time of initiating treatment for PDR), ocular and systemic safety, adherence to and frequency of follow-up of each regimen, and patient preferences should be weighed by patients with physician guidance when deciding whether to consider initiating anti-VEGF or PRP for PDR.

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Article Information

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

Accepted for Publication: March 9, 2017.

Published Online: May 8, 2017. doi:10.1001/jamaophthalmol.2017.0837

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

Concept and design: Hutton, Stein, Bressler, Jampol, Glassman.

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

Drafting of the manuscript: Hutton, Bressler, Jampol, Glassman.

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

Statistical analysis: Hutton.

Obtained funding: Bressler, Jampol, Glassman.

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

Supervision: Bressler, Glassman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bressler reports grants from Bayer, Novartis, Regeneron, and Roche outside the submitted work. Dr Browning reports grants from Regeneron, Alcon, Genentech, Novartis, Ohr, Alimera, and Aerpio outside the submitted work. Dr Glassman reports grants from the National Institutes of Health during the conduct of the study and grants and nonfinancial support from Genentech outside the submitted work. Dr Hutton reports grants from Jaeb Center for Health Research during the conduct of the study. Dr Jampol reports grants from the National Eye Institute. A complete list of all DRCR.net investigator financial disclosures can be found at http://www.drcr.net. No other disclosures were reported.

Funding/Support: This study was supported through a cooperative agreement from grants EY14231, EY23207, and EY18817 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. Genentech provided ranibizumab for the study and funds to the DRCR.net to defray the study’s clinical site costs.

Role of the Funder/Sponsor: The funding organizations 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 of the manuscript or the decision to submit the manuscript for publication. Per the Diabetic Retinopathy Clinical Research Network Industry Collaboration Guidelines (available at http://www.drcr.net), the Diabetic Retinopathy Clinical Research Network had complete control over the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

Group Information: The members of the Diabetic Retinopathy Clinical Research Network investigators and staff who participated in this study are listed here. Sites are listed in order by number of patients enrolled into the study.

Charlotte Eye, Ear, Nose and Throat Association, Charlotte, North Carolina: Justin C. Brown; Andrew N. Antoszyk; David Browning; Angela K. Price; Sherry L. Fredenberg; Jenna T. Herby; Merri F. Walker; Christina J. Fleming; Ashley A. McClain; Angella S. Karow; Autumn C. Grupp; Kelly R. Gallagher; Sarah A. Ennis; Donna McClain; Joan P. Mondello; Autumn K. Finch; Kathryn Kimrey; Loraine M. Clark; Lisa A. Jackson; Lynn Watson; Jeff A. Kuopus; Robin Kerr; Swann J. Bojaj; Susannah J. Held; Uma M. Balasubramaniam; Michael D. McOwen; and Matt Dunlap.

Elman Retina Group, Baltimore, Maryland: Michael J. Elman; Henry A. Leder; JoAnn Starr; Jennifer L. Belz; Charlene K. Putzulo; Dena Y. Salfer-Firestone; Perel M. Simpson; Pamela V. Singletary; Jennifer L. Simmons; Teresa Coffey; Dallas R. Sandler; Ashley Davis; Ashley M. Metzger; Peter Sotirakos; Terri Cain; and Daniel J. Ketner.

Florida Retina Consultants, Lakeland, Florida: Scott M. Friedman; Nader Moinfar; Kimberly A. Williamson; Karen Sjoblom; Katrina L. Dawson; Damanda F. Fagan; Paige N. Walters; Steve Carlton; and Allen McKinney.

Paducah Retinal Center, Paducah, Kentucky: Carl W. Baker; Ron H. Tilford; Tracey M. Caldwell; Lynnette F. Lambert; Margaret J. Orr; Mary J. Palmer; Tracey R. Martin; Alecia B. Camp; Samantha Kettler; and Tana R. Williams.

Southeast Retina Center, Augusta, Georgia: Dennis M. Marcus; Harinderjit Singh; Siobhan O. Ortiz; Teresa J. Acklie; Michele Woodward; Courtney N. Roberts; Geri L. Floyd; Judith Hendrickson; Lindsay Allison Foster; Christy Coursey; Virginia Mims; Jared C. Gardner; Kimbi Y. Overton; and Ken Ivey.

Retina Research Center, Austin, Texas: Brian B. Berger; Chirag D. Jhaveri; Tori Moore; Ivana Gunderson; Rachel A. Walsh; Ginger J. Manhart; Jenny J. Tracy; Dietrich Riepen; Boris Corak; Chelsey A. Bravenec; Brandon Nguyen; Ryan M. Reid; Yong Ren; Christopher C. Stovall; and Ben Ostrander.

California Retina Consultants, Santa Barbara, California: Dante J. Pieramici; Alessandro A. Castellarin; Sarah Fishbein; Michelle S. Hanna; Erica D. Morasse; Gina Hong; Jack Giust; Lisha Wan; Melvin D. Rabena; Sara Esau; Jerry Smith; Kelly Avery; Layne J. Bone; Aimee Walker; Matthew Giust; Nitce L. Ruvalcaba; and Aimee H. Shook.

Carolina Retina Center, Columbia, South Carolina: Jeffrey G. Gross; Michael A. Magee; Barron C. Fishburne; Amy M. Flowers; Christen Ochieng; Riley Stroman; Angelique S.A. McDowell; Randall L. Price; and Hunter Matthews.

Texas Retina Associates, Lubbock, Texas: Michel Shami; Sushma K. Vance; Yolanda Saldivar; Keri S. Neuling; Brenda K. Arrington (C,P,V); Ashaki Meeks; Natalie R. Garcia; Kayla Blair; Janet Medrano; and Ginger K. Rhymes.

Fort Lauderdale Eye Institute, Plantation, Flordia: Stuart K. Burgess; Tirso M. Lara; Noel H. Pereda; Cindy V. Fernandez; Evelyn Quinchia; Deborah Davis; and Karen Workman.

New England Retina Associates, Trumbull, Connecticut: Nauman A. Chaudhry; Sumit P. Shah; Gregory M. Haffner; Emiliya German; Laura A. Fox; JoAnna L. Pelletier; Jennifer M. Matteson; Shannan Moreau; Kristin E. Brown; Michelle Esler; Alison Fontecchio; Emily Morse; Marie Grace Laglivia; Justin A. Cocilo; Greg McNamara; Stefanie R. DeSantis; Marissa L. Scherf; and Angela LaPre.

Valley Retina Institute, McAllen, Texas: Victor Hugo Gonzalez; Nehal R. Patel; Rohit Adyanthaya; Roberto Diaz-Rohena; Deyla Anaya; Crystal A. Alvarez; Ruth Iracheta; Edna E. Cruz; Jessica Rodriguez; Gabriela Zavala; Kethsaly J. Salinas; Tabitha Trevino; Krystle R. Lozano; Karina Miranda; Monica R. Cantu; Maricela Garza; Hector Jasso; Rebecca R. Flores; Rachel Rodriguez; Samuel Alonso; Amanda L. Sandoval; Santos Garza; John Trevino; Lazaro Aguero; and Monique Montemayor.

Retina Northwest, Portland, Oregon: Mark A. Peters; Paul S. Tlucek; Michael S. Lee; Colin Ma; Stephen Hobbs; Stephanie L. Ho; Amanda C. Milliron; Marcia Kopfer; Joe Logan; and Christine Hoerner.

Retinal Consultants of San Antonio, San Antonio, Texas: Calvin E. Mein; R. Gary Lane; Moises A. Chica; Sarah Elizabeth Holy; Lita Kirschbaum; Vanessa D. Martinez; Jaynee Baker; Adriana A. Lopez; Christa G. Kincaid; Sara L. Schlichting; Brenda Nakoski; Christopher Sean Wienecke; Elaine Castillo; and Clarissa M. Marquez.

Vitreo-Retinal Associates, Worcester, Massachusetts: Frank J. McCabe; Brad J. Baker; Melvyn H. Defrin; Marie V. Lampson; Heather Pratte; Selena A. Baron; and Aundrea S. Borelli.

National Ophthalmic Research Institute, Fort Myers, Florida: A. Thomas Ghuman; Paul A. Raskauskas; Glenn Wing; Ashish G. Sharma; Joseph P. Walker; Eileen Knips (C,P); Natalie N. Torres; Crystal Y. Peters; Cheryl Ryan; Laura Greenhoe; Cheryl Kiesel; Rebecca J Youngblood; Anita H. Leslie; Danielle Turnbo; Etienne C. Schoeman; and Raymond K. Kiesel.

Retina Consultants of Houston, Houston, Texas: Charles C. Wykoff; Eric Chen; David M. Brown; Matthew S. Benz; Tien P. Wong; Amy C. Schefler; Richard H. Fish; James C. Major; Rosa Y. Kim; Meredith Lipman; Ashley E. Chancey; Amy Hutson; Cassie Cone; Stacy M. Supapo; Nubia Landaverde; Belinda A. Almanza; Brenda Dives; Veronica A. Sneed; Eric N. Kegley; Cary A. Stoever; and Beau A. Richter.

Loma Linda University Health Care, Department of Ophthalmology, Loma Linda, California: Joseph T. Fan; Mukesh Bhogilal Suthar; Michael E. Rauser; Gisela Santiago; Brandi J. Perez; Liel Marvyn Cerdenio; Kara E. Halsey; William H. Kiernan; Raquel Hernandez; Diana Povero; and Jesse Knabb.

Casey Eye Institute, Portland, Oregon: Andreas K. Lauer; Christina J. Flaxel; Ann D. Lundquist; Mitchell Schain; Shelley A. Hanel; Susan K. Nolte; Shirley D. Ira; Scott R. Pickell; Peter N. Steinkamp; Jocelyn T. Hui; Jordan Barth; Dawn M. Ryan; Chris S. Howell; and Michelle Brix.

Retina Associates of Cleveland, Inc, Beachwood, Ohio: Michael A. Novak; David G. Miller; Llewelyn J. Rao; Jerome P. Schartman; Joseph M. Coney; Lawrence J. Singerman; Susan C. Rath; Veronica A. Smith; Larraine Stone; Elizabeth McNamara; Kimberly A. DuBois; Vivian Tanner; Mary A. Ilc; Kim Drury; Cecelia Rykena; Trina M. Nitzsche; Gregg A. Greanoff; and John C. DuBois.

Family Eye Group, Lancaster, Pennsylvania: Michael R. Pavlica; Noelle S. Matta; Alyson B. Keene; Cristina M. Brubaker; and Christine M. Keefer.

Ocala Eye Retina Consultants, Ocala, Florida: Chander N. Samy; Robert J. Kraut; Kathy Shirley; Linsey Corso; Karen Ely; Elizabeth Scala; Vanessa Alava; and Stewart Gross.

Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan: Thomas W. Gardner; Grant M. Comer; Pamela S. Campbell; Lindsay M. Godsey; Linda Fournier; Moe Hesselgrave; Timothy Steffens; Robert Prusak; Hillary Bernard; Linda Goings; and Alexis L. Smith.

Retina Vitreous Center, Grand Blanc, Michigan: Robin D. Ross; Susan M. Sanford; Nicole Martini Markiewicz; Tracy M. Utley; Shannon Henderson; Mary D. Walker; Joanie H. Lippincott; and Patricia Streasick.

Joslin Diabetes Center/Harvard Vanguard Medical Associates, Boston, Massachusetts: Jennifer K. Sun; Paolo S. Silva; Lloyd Paul Aiello; Paul Arrigg; Margaret E. Stockman; Hanna Kwak; Ann Kopple; Jerry D. Cavallerano; Rita K. Kirby; Leila Bestourous; Elizabeth S. Weimann; and Robert W. Cavicchi.

Denver Health Medical Center, Denver, Colorado: Hugo Quiroz-Mercado; Leif S. Ryman; Teresa E. Rudesyle; Daniela Santos Canto; Guillermo Salcedo-Villanueva; Chelsea Lynn Mastin; Rosemary C. Rhodes; Carolyn J. Jackson; and Regina Victoria.

Raj K. Maturi, MD, Indianapolis, Indiana: Raj K. Maturi; Ashley M. Harless; Carolee K. Novak; Laura A. Bleau; Nicole Ellingwood; Thomas Steele; Missy Livengood; Alisha Bildner; Abby Maple; and Charlotte Harris.

University of Florida College of Medicine, Department of Ophthalmology, Jacksonville Health Science Center, Jacksonville, Florida: Kakarla V. Chalam; Ghulam Shabbir Hamdani; Shamim A. Haji; Wenhua Li; Kumar Sambhav; Ashley Cowart; Nicholas Freeman; and Jose J. Carrion.

Southeastern Retina Associates, Knoxville, Tennessee: Joseph M. Googe; Stephen L. Perkins; Nicholas G. Anderson; Kristina Oliver; Lisa Lovelady; Christy Berry; Cecile Hunt; Jennifer Beerbower; Ann Arnold; Nicole Grindall; Patricia Coppola; Kathy L. Schulz; Jerry K. Whetstone; Sarah M. Oelrich; Raul E. Lince; and Justin Walsh.

Medical College of Wisconsin Milwaukee, Wisconsin: Judy E. Kim; Dennis P. Han; David V. Weinberg; William J. Wirostko; Thomas B. Connor; Vesper V. Williams; Krissa L. Packard; Tracy L. Kaczanowski; Judy Flanders; Vicki Barwick; Pat A. Winter; Dennis B. Backes; Mara Goldberg; Joseph R. Beringer; and Kathy J. Selchert.

Medical Center Ophthalmology Associates San Antonio, Texas: Michael A. Singer; Darren J. Bell; Catherine Ellis; Tamara M. Urias; Beatrice A. Guajardo; Roxanne Gomez; Ann-Marie Mora; Celia Maria Pena; Vincent Segovia; and Rosa Escobar.

Retina-Vitreous Surgeons of Central New York, Syracuse, New York: G. Robert Hampton; Jamin S. Brown; Laurie J. Sienkiewycz; Cindy J. Grinnell; Lynn M. Kwasniewski; Michelle L. Manley; Nicole E. Robarge; Peter B. Hay; and Teresa M. DeForge.

Wolfe Eye Clinic, West Des Moines, Iowa: Jared S. Nielsen; Kyle J. Alliman; Marianne Parker; Bethany George; Jennifer L. Coleman; Jamie Spillman; Marilyn A. Johnson; Holly Keenan; Bailey R. Bennett; Jay Rostvold; and Jodi Weier.

Austin Retina Associates, Austin, Texas: Robert W. Wong; Shelley Day; Peter A. Nixon; Chris A. Montesclaros; Carrie E. Leung; Phill Le; Margaret A. Rodriguez; Mary Laremont; Cory Mangham; and Codey L. Harborth.

Retinal and Ophthalmic Consultants, Northfield, New Jersey: Brett T. Foxman; Scott G. Foxman; Natalie S. Mahan; and Chastity Mendez.

University of Rochester, Rochester, New York: David Allen DiLoreto; George W. O'Gara; Andrea M. Czubinski; Kari M. Steinmetz; Melissa S. Keim; Yvonne F. Yu; Salina M. Tongue; Dan A Castillo; Laura Guzman; Lynn Singer; Rachel Hollar; Taylor A. Pannell; Brittany S. Richardson; Brandi N. Deats; Steven DeRidder; and Tke Long.

University of Washington Medical Center, Seattle, Washington: James L. Kinyoun; Gurunadh Atmaram Vemulakonda; Susan A. Rath; Patricia K. Ernst; Juli A. Pettingill; Brad C. Clifton; James D. Leslie; and Ronald C. Jones.

Spokane Eye Clinic, Spokane, Washington: Robert S. Wirthlin; Eric S. Guglielmo; Eileen A. Dittman; Dylan C. Waidelich; Christina Owens; Vicki M. Stanton; Adeline M. Stone; Ashley Nicole Oakes; and Cristofer J. Garza.

Bay Area Retina Associates, Walnut Creek, California: Stewart A. Daniels; Tushar M. Ranchod; Stacey Touson; Shannon R. Earl; Jessica Garcia; Melissa C. Bartlett; Christine Fernando; Jose Carlos Suazo; Grace M. Marudo; Matthew D. Hughes; Fred Hanamoto; Cathy Walker; Betty Hom; Leah M. McNeil; and Yesenia Cerna.

Retina Specialists of Michigan, Grand Rapids, Michigan: Thomas M. Aaberg; Scott J. Westhouse; Holly L. Vincent; Rebecca Malone; Kristine L. VanDerKooi; Casey Le Roy; and Kathy L. Karsten.

Retina and Vitreous of Texas, Houston, Texas : Joseph A. Khawly; H. Michael Lambert; Pam S. Miller; Valerie N. Lazarte; Debbie Fredrickson; Colin Blank; Donald K. Lowd; Desiree Lopez; Jason E. Muniz; and Lorena R. Martinez.

Baylor Eye Physicians and Surgeons, Houston, Texas: Petros Euthymiou Carvounis; Robert E. Coffee; Pejman Hemati; Cindy J. Dorenbach; Annika S. Joshi; April Leger; Dana B. Barnett; and Joseph F. Morales.

Retina Vitreous Consultants, Monroeville, Pennsylvania: Karl R. Olsen; P. William Conrad; Pamela P. Rath; Judy C. Liu; Bernard H. Doft; Robert L. Bergren; Lori A. Merlotti; Mary E. Kelly; Holly M. Mechling; Jennifer L. Chamberlin; Missy A. Forish; Veronica L. Bennett; Christina M. Schultz; Grace A. Rigoni; Lois Stepansky; Kimberly A. Yeckel; Kellianne Marfisi; Christina R. Fulwylie; Julie Walter; Courtney L. Foreman; David Steinberg; Brandi L. Sherbine; Amanda Fec; and Keith D. McBroom.

University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania: Alexander J. Brucker; Benjamin J. Kim; Sheri Drossner; Joan C. DuPont; Armin Farazdaghi; Laurel Weeney; Michael Bodine; Beth Serpentine; Cheryl Devine; Jim M. Berger; and William Nyberg.

Retina Associates of Florida, Tampa, Florida: Ivan J. Suner; Marc C. Peden; Mark E. Hammer; Janet R. Traynom; Rochelle DenBoer; Susan Ramsey; Heidi Vargo; Debra Jeffres; and Anita Kim Malzahn.

Wilmer Eye Institute at Johns Hopkins, Baltimore, Maryland: Sharon D. Solomon; Susan Bressler; Lisa K. Levin; Mary Frey; Deborah Donohue; Rita L. Denbow; Keisha Murray; David Emmert; Joe Belz; Janis Graul; Jacquelyn McDonald; and Nick Rhoton.

Montefiore Medical Center, Bronx, New York: Umar Khalil Mian; Rebecca L. Riemer; Louise V. Wolf; Evelyn Koestenblatt; Erica Otoo; Irina Katkovskaya; Christine Kim; Kevin A. Ellerbe; Caroline Costa; and Kenneth Boyd.

Retinal Diagnostic Center, Campbell, California: Amr Dessouki; Joel M. Barra; Jessenia Perez; Rose Monahan; Kelly To; Hienmy Dang; and Tim Kelley.

Rush University Medical Center Chicago, Illlinois: Mathew W. MacCumber; Eileen E. Tonner; Danielle R. Carns; Denise L. Voskuil-Marre; Evan R. Rosenberg; and Kisung Woo.

Texas Retina Associates, Dallas, Texas: Gary E. Fish; Sally Arceneaux; Karen Duignan; Nicholas Hesse; and Michael Mackens.

North Shore University Health System, Glenview, Illinois: Manvi P. Maker; Mira Shiloach; Courtney Kastler; and Lynn Wasilewski.

Retina Associates of Kentucky, Lexington, Kentucky: Thomas W. Stone; John W. Kitchens; Diana M. Holcomb; Jeanne Van Arsdall; Edward A. Slade; and Michelle Buck.

Southern California Desert Retina Consultants, Palm Desert, California: Clement K. Chan; Maziar Lalezary; Kimberly S. Walther; Tiana Gonzales; Lenise E. Myers; and Kenneth M. Huff.

Retinal Consultants of Arizona, Phoenix, Arizona: Karim N. Jamal; David T. Goldenber; Sachin Mehta; Scheleen R. Dickens; Jessica L. Miner; Heather Dunlap; Lydia Saiz; Dayna Bartoli; John J. Bucci; and Rohana Yager.

Sarasota Retina Institute, Sarasota, Florida: Melvin Chen; Peggy A. Jelemensky; Tara L. Raphael; Mark Sneath; and Evelyn Inlow.

The Retina Institute, St. Louis, Missouri:Kevin J. Blinder; Ginny S. Nobel; Rhonda F. Weeks; Maria A. Stuart; Brook G. Pulliam; Kelly E. Pepple; Lynda K. Boyd; Timothy L. Wright; Dana L. Gabel; and Jarrod Wehmeier.

Disclaimer: Dr Bressler is the Editor of JAMA Ophthalmology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

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