Abstract
Purpose:
This work compares the relative cost utility of ranibizumab and aflibercept with and without verteporfin photodynamic therapy (vPDT) for the treatment of polypoidal choroidal vasculopathy.
Methods:
A retrospective cost and outcomes analysis of the PLANET (Efficacy and Safety of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy) and EVEREST II (Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy) studies was performed. Clinical utilization and outcomes were based on data from these clinical trials, and costs were obtained from Medicare fee schedules. Cost utility was derived from published visual outcomes and expressed as quality-adjusted life-years (QALYs). Cost per QALY and cost per line of vision gained for each treatment strategy (in US dollars) were assessed as the main outcome measure.
Results:
The 1-year facility (nonfacility) costs per QALY were $295,744.41 ($260,088.19), $209,574.09 ($182,831.77), $211,072.63 ($188,425.33), and $212,275.22 ($189,703.05) for ranibizumab as-needed monotherapy, ranibizumab as-needed with combination therapy, aflibercept monotherapy, and aflibercept with delayed vPDT combination therapy, respectively.
Conclusions:
Ranibizumab as-needed monotherapy was the least clinically effective and least cost efficient over 1 year. Ranibizumab as-needed with combination therapy, aflibercept monotherapy, and aflibercept with deferred vPDT combination therapy all had similar overall cost utility at 1 year. If bevacizumab were to be substituted for ranibizumab, the cost per QALY could be reduced by approximately a factor of 5, showing the benefit of bevacizumab for increasing the cost utility of polypoidal choroidal vasculopathy treatment.
Keywords: aflibercept, age-related macular degeneration, aneurysmal type 1 neovascularization, outcomes, polypoidal choroidal vasculopathy, ranibizumab
Introduction
The disease burden and corresponding health care costs of treating age-related macular degeneration (AMD) are increasing globally. 1 -3 Polypoidal choroidal vasculopathy (PCV), also referred to as aneurysmal type 1 neovascularization, is a subtype of AMD most commonly found in patients of East Asian descent but also in those of South Asian, African, Middle Eastern, and European descent. 4,5 This condition is important to distinguish from classic exudative AMD because PCV has a less robust response to antivascular endothelial growth factor (anti-VEGF) therapy.
Two recent randomized, controlled clinical trials examined different treatment algorithms for treating PCV with anti-VEGF monotherapy or combined anti-VEGF and verteporfin photodynamic therapy (vPDT)—the Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy trial (EVEREST II) and the Efficacy and Safety of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy trial (PLANET). 6,7 The EVEREST II trial compared the efficacy of ranibizumab 0.5 mg/0.05 mL monotherapy with ranibizumab and vPDT combination therapy. PDT or a sham procedure was performed at baseline along with 3 monthly ranibizumab injections followed by anti-VEGF retreatment on an as-needed basis. 7 Similarly, the PLANET trial compared aflibercept monotherapy with combination therapy for aflibercept and delayed vPDT. Both arms received 2-mg intravitreal aflibercept injections at weeks 0, 4, and 8 followed by a fixed dosing interval with aflibercept every 8 weeks. 6 The combination arm received vPDT only as a rescue at 3 months when necessary.
The present study compared the relative cost utility of each treatment strategy for PCV based on data derived from these 2 prospective, randomized trials.
Methods
Methods for this paper were modeled after a prior cost-analysis study. 8 Published usage and outcomes data from the EVEREST II and PLANET randomized clinical trials were the data source for the cost analysis. The natural history data of PCV were also taken into account. 9
Each EVEREST II and PLANET protocol treatment scenario spanned 1 year and presumed 1 new patient comprehensive eye examination (Current Procedural Terminology [CPT] 92004), 1 initial indocyanine green angiography and fluorescein angiography (CPT 92242), 11 intermediate monthly follow-up examinations (CPT 92012), 12 total monthly optical coherence tomography images (CPT 92134), and 3 fundus photographs (CPT 92250). The studies did not specify whether all imaging studies were reimbursable, but they would be so in parallel and not affect the differential costs of each treatment strategy. The numbers of intravitreal injections of ranibizumab or aflibercept and vPDT studies were based on treatment protocols in the EVEREST II and PLANET trials.
Costs of medications, procedures, office visits, and diagnostic studies were based on 2018 Medicare fee data, collected from the Centers for Medicare and Medicaid Services, and identified based on CPT codes for both facility and nonfacility procedures using the national payment amount fees, which is carrier locality code “0000000.” 10 The Medicare-allowable costs per medication, procedure, and service are summarized in Table 1, and the overall cost and utilization of health care services are summarized in Table 2. All costs are reported in 2018 US dollars and include 1 year of treatment only.
Table 1.
Medicare-Allowable Costs for Antivascular Endothelial Growth Factor and Verteporfin Photodynamic Therapy Treatment for Polypoidal Choroidal Vasculopathy.
| Nonfacility | Facility | |||||
|---|---|---|---|---|---|---|
| Treatment | CPT code | Medication cost, $ | Procedure fee, $ | Total, $ | Procedure fee, $ | Total, $ |
| Ranibizumab | 67028 | 1947.80 | 104.40 | 2052.20 | 102.96 | 2050.76 |
| Aflibercept | 67028 | 2018.57 | 104.40 | 2122.97 | 102.96 | 2121.53 |
| Verteporfin | 67220 | 1698.42 | 548.27 | 2246.69 | 514.07 | 2212.49 |
Abbreviation: CPT, Current Procedural Terminology.
Table 2.
Estimated Cost and Utilization of Clinical Services.
| Non-facility | Facility | 1-year letters gained | Natural history PCV 1-year letters lost | Total estimated visual benefit | |||||
|---|---|---|---|---|---|---|---|---|---|
| No. of injections | No. of PDT treatments | 1-year cost of treatment, $ | 1-year cost out of treatment + exams, visits, $ | 1-year cost of treatment, $ | 1-year cost out of treatment + exams, visits, $ | ||||
| EVEREST II | |||||||||
| Ranibizumab only | 7.3 | 0 | 14,981.08 | 17,034.88 | 14,970.57 | 16,584.09 | 5.1 | 4.5 (0.09 logMAR) | 9.6 |
| Ranibizumab and vPDT |
5.2 | 1.5 | 14,041.49 | 16,095.29 | 13,982.70 | 15,596.22 | 8.3 | 4.5 (0.09 logMAR) | 12.8 |
| Bevacizumab only | 7.3 | 0 | 1127.12 | 3180.92 | 1116.61 | 2730.13 | 5.1 | 4.5 (0.09 logMAR) | 9.6 |
| Bevacizumab and PDT |
5.2 | 1.5 | 4172.92 | 6226.72 | 4114.13 | 5727.65 | 8.3 | 4.5 (0.09 logMAR) | 12.8 |
| PLANET | |||||||||
| Aflibercept only | 8.1 | 0 | 17,196.02 | 19,249.82 | 17,184.36 | 18,797.88 | 10.7 | 4.5 (0.09 logMAR) | 15.2 |
| Aflibercept and deferred vPDT |
8 | 0.2 | 17,433.07 | 19,486.87 | 17,414.71 | 19,028.23 | 10.8 | 4.5 (0.09 logMAR) | 15.3 |
Abbreviations: EVEREST II, Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy trial; PCV, polypoidal choroidal vasculopathy; vPDT, verteporfin photodynamic therapy; PLANET, Efficacy and Safety of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy trial.
Cost utility was expressed as quality-adjusted life-years (QALYs) using a conversion factor of 0.03 QALY per line-year of vision, a convention used in prior studies, which presumes second eye utility. 8,11 Eyes were presumed to have poorer vision for 1 year only. A hypothetical treatment strategy using bevacizumab as a replacement for ranibizumab in the EVEREST II trial was also used. This model presumed that bevacizumab would have identical visual outcomes and total number of injections, and that the total cost of each bevacizumab administration was $50.
All calculations were performed using Microsoft Excel (version 15.34, Microsoft Corp) and R (version 3.1.10, R-project, https://www.r-project.org/). No patient records were reviewed, and data were obtained from previously published data from trials of which the present authors were not coinvestigators.
Results
The estimated total visual benefits (when accounting for the natural history of vision lost with no treatment) after 1 year of treatment in the EVEREST II trial were 9.6 and 12.8 letters for intravitreal ranibizumab monotherapy and ranibizumab with prompt vPDT, respectively. The corresponding published benefits in the PLANET trial for aflibercept monotherapy and aflibercept with deferred vPDT were 15.2 and 15.3 letters, respectively (see Table 2).
The facility (nonfacility) cost of per letter-year gained for as-needed ranibizumab monotherapy, as-needed ranibizumab combination therapy, aflibercept monotherapy, and aflibercept with delayed combination therapy was $1774.47 ($1560.53), $1257.44 ($1096.99), $1266.44 ($1130.55), and $1273.65 ($1138.22), respectively. The 1-year facility (nonfacility) costs per QALY were $295,744.41 ($260,088.19), $209,574.09 ($182,831.77), $211,072.63 ($188,425.33), and $212,275.22 ($189,703.05). If bevacizumab was substituted for ranibizumab in the incremental cost-effectiveness ratio (ICER) model, assuming equivalent clinical efficacy, the cost per QALY of as-needed bevacizumab monotherapy would be $57,368.75 ($49,522.50). The cost per QALY of as-needed bevacizumab and vPDT would be $48,676.28 ($42,704.40) (Table 3).
Table 3.
Cost and Visual Outcomes From EVEREST II and PLANET at 1 Year.
| Facility billing | Nonfacility Billing | ||||||
|---|---|---|---|---|---|---|---|
| Treatment plan | Letters gained | TEVB | Mean age | Cost per letters gained (TEVB), $ | Cost for 1 QALY, $ | Cost per letters gained (TEVB), $ | Cost for 1 year, $ |
| EVEREST II | |||||||
| Ranibizumab only | 5.1 | 9.6 | 68 | 1774.47 | 295,744.41 | 1560.53 | 260,088.19 |
| Ranibizumab and vPDT | 8.3 | 12.8 | 68.2 | 1257.44 | 209,574.09 | 1096.99 | 182,831.77 |
| PLANET | |||||||
| Afblicercept | 10.7 | 15.2 | 70.4 | 1266.44 | 211,072.63 | 1130.55 | 188,425.33 |
| Aflibercept and deferred vPDT |
10.8 | 15.3 | 70.8 | 1273.65 | 212,275.22 | 1138.22 | 189,703.05 |
| Bevacizumab simulation | |||||||
| Bevacizumab only | 5.1 | 9.6 | 68 | 344.21 | 57,368.75 | 297.14 | 49,522.50 |
| Bevacizumab and vPDT | 8.3 | 12.8 | 68.2 | 292.06 | 48,676.28 | 256.23 | 42,704.40 |
Abbreviations: EVEREST II, Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy trial; vPDT, verteporfin photodynamic therapy; PLANET, Efficacy and Safety of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy trial; QALY, quality-adjusted life-years; TEVB, total estimated visual benefit.
The ICER of US dollars/QALY of ranibizumab pro re nata monotherapy was –$48,937/QALY compared with ranibizumab and vPDT, indicating the former was both more costly and yielded less utility. The ICER and (total costs) for aflibercept monotherapy ($19,249.82) compared with aflibercept and deferred vPDT ($19,486.87) was $395,069/QALY. The ICER and (total costs) for as-needed ranibizumab monotherapy ($17,034.88) compared with aflibercept monotherapy with a fixed dosing ($19,249.82) was $65,921/QALY. The ICERs for ranibizumab and vPDT ($16,095.29) compared with aflibercept and deferred vPDT ($19,486.87) and aflibercept monotherapy ($19,249.82) were $226,105/QALY and $219,065/QALY, respectively. The ICER of bevacizumab monotherapy ($3180.92) vs bevacizumab and vPDT ($6226.72) is $158,635/QALY. The ICER of bevacizumab monotherapy ($3180.92) compared with aflibercept monotherapy ($19,249.82) is $478,421/QALY. The ICER of bevacizumab and vPDT ($6226.72) vs aflibercept and deferred vPDT ($19,486.87) and aflibercept monotherapy ($19,249.82) is $884,010/QALY and $904,382/QALY, respectively (Table 4).
Table 4.
Incremental Cost-Effectiveness Ratio of Treatment Options.a
| Total cost | Letters gained | Difference in letters | Utility difference (QALY) | ICER ($/QALY) | |
|---|---|---|---|---|---|
| Ranibizumab only | $17,034.88 | 9.6 | 3.2 | 0.0192 | –$48,937 |
| Ranibizumab and vPDT | $16,095.29 | 12.8 | |||
| Aflibercept only | $19,249.82 | 15.2 | 0.1 | 0.0006 | $395,069 |
| Aflibercept and deferred vPDT | $19,486.87 | 15.3 | |||
| Ranibizumab only | $17,034.88 | 9.6 | 5.6 | 0.0336 | $65,921 |
| Aflibercept only | $19,249.82 | 15.2 | |||
| Ranibizumab and vPDT | $16,095.29 | 12.8 | 2.5 | 0.0150 | $226,105 |
| Aflibercept and deferred vPDT | $19,486.87 | 15.3 | |||
| Ranibizumab and vPDT | $16,095.29 | 12.8 | 2.4 | 0.0144 | $219,065 |
| Aflibercept only | $19,249.82 | 15.2 | |||
| Bevacizumab only | $3180.92 | 9.6 | 3.2 | 0.0192 | $158,635 |
| Bevacizumab and vPDT | $6226.72 | 12.8 | |||
| Bevacizumab only | $3180.92 | 9.6 | 5.6 | 0.0336 | $478,241 |
| Aflibercept only | $19,249.82 | 15.2 | |||
| Bevacizumab and vPDT | $6226.72 | 12.8 | 2.5 | 0.0150 | $884,010 |
| Aflibercept and deferred vPDT | $19,486.87 | 15.3 | |||
| Bevacizumab and vPDT | $6226.72 | 12.8 | 2.4 | 0.0144 | $904,382 |
| Aflibercept only | $19,249.82 | 15.2 |
Abbreviations: ICER, incremental cost-effectiveness ratio; vPDT, verteporfin photodynamic therapy; QALY, quality-adjusted life-years.
aShading denotes pairs of rows compared in each ICER analysis.
Conclusions
This cost-analysis study model found as-needed ranibizumab monotherapy of PCV to have the least clinical efficacy and the least favorable cost utility over 1 year. As-needed ranibizumab with combination therapy, aflibercept monotherapy, and aflibercept with deferred vPDT combination therapy all had similar overall cost utility at 1 year. If bevacizumab were to be substituted for ranibizumab, the cost/QALY could be reduced by approximately a factor of 5 compared with treatment with aflibercept. Given these findings, assuming similar clinical efficacy for aflibercept and ranibizumab, the substitution of bevacizumab could improve the cost utility of PCV treatment. Furthermore, the results suggest that vPDT is highly cost-effective, reducing the number of injections while improving visual outcomes.
As the prevalence of AMD and likely that of PCV continues to grow, treatment expenses become increasingly relevant. The high cost burden of anti-VEGF medications has led to investigations of the clinical outcomes with less-frequent treatment strategies such as as-needed, treat and extend, or other longer intervals of treatment. 12 Recent evidence suggests that as-needed treatments generally have inferior visual outcomes compared with fixed monthly or treat-and-extend protocols. 13 In addition, anti-VEGF resistance is more prevalent in PCV than in typical exudative AMD in both white and Asian populations. 14,15 In addition, other possibly less costly agents have been evaluated or are in development. The present study found, for example, that if bevacizumab were to be substituted for ranibizumab, assuming equivalent efficacy of these medications, the cost/QALY could be reduced by approximately a factor of 5. These findings may demonstrate the utility of treatment with and without vPDT and may be directly applicable for practitioners.
Although the expenses used in the present study are only estimates—both studies may have had intermediate examinations without actual reimbursement—this study captures a theoretical comparison of 2 different treatment strategies and overall costs. This study’s limitations are inherent in the studies on which its data are based, and these results cannot be extrapolated beyond 1 year of data. The EVEREST II trial compared combined immediate vPDT and ranibizumab vs ranibizumab monotherapy; the PLANET trial compared aflibercept therapy with aflibercept and delayed vPDT. However, owing to strict criteria for obtaining delayed vPDT in the latter trial, only a minority (approximately less than 1/5) of patients actually received vPDT, further limiting the comparability of the trials. 6,7
Although it is possible that asymmetric treatment protocols with different medications may somewhat limit comparability, recent trial evidence has shown that in treat-and-extend protocols for AMD, the same number of average injections were needed in both ranibizumab and aflibercept arms. 16 Thus, we suspect that relative costs might not vary much proportionally. Furthermore, the cost-effectiveness of aflibercept with immediate vPDT is unknown, and clinical trial data have suggested that immediate vPDT may decrease anti-VEGF burden more than delayed vPDT. 17 Because costs of medication, imaging, and other health services vary abroad, the conclusions and applications of the current model may be limited outside the United States. Some nationalized health services mandate therapeutic regimens, including limiting anti-VEGF use to lower-cost alternatives such as bevacizumab. 12
In conclusion, as-needed ranibizumab combination therapy, aflibercept monotherapy, and aflibercept with deferred vPDT combination therapy all demonstrate similar cost utility in the treatment of PCV at 1 year. If clinical efficacy is equivalent for aflibercept and ranibizumab, bevacizumab use increases the cost utility of PCV treatment by a factor of approximately 5. These data may be useful for practitioners in their evaluation of the utility of VPDT in treating PCV.
Footnotes
Authors’ Note: Dr. Lin is currently affiliated with the Albert Einstein College of Medicine, Bronx, New York, and Dr. Mehta is now at New York University School of Medicine and New York University Ophthalmology Associates.
Ethical Approval: No human participants were involved in this study, and institutional review board approval was not needed.
Statement of Informed Consent: Informed consent was not required as no human participants were involved in this study.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Sakurada is a paid speaker for Bayer and Novartis. Dr Modi is a consultant to Genentech, Allergan, and Alimera. The other authors have nothing to declare.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Paula W. Feng, MD 
https://orcid.org/0000-0003-4356-2452
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