To perform 11- and 2-year health care sector (ophthalmic) and societal cost perspective reference case, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for ...neovascular age-related macular degeneration (NVAMD).
Cost-utility analysis.
The authors performed 11-year and 2-year ophthalmic and societal cost perspective, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for neovascular age-related macular degeneration (NVAMD). We employed patient utilities, bilateral outcomes, 2018 U.S. dollars, vision-related mortality, a Medicare fee schedule, and CATT (Comparison of Age-Related Macular Degeneration Treatments) study and VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) trial. Cochrane data were also used. Setting: Center for Value-Based Medicine. Patient/study population: patients with NVAMD. Intervention: Cost-utility analyses using published data. Data-modeled 10-year vision outcomes were modeled forward to year 11. Main outcome measurement: These included cost-utility ratios (CURs), costs, and quality-adjusted life-years (QALYs) gained. $100,00/QALY was considered the US cost-effectiveness upper limit.
Bevacizumab and ranibizumab each conferred an 11-year, 1.339 QALY gain versus observation. Aflibercept conferred a 1.380 QALY gain. Aflibercept conferred greater QALY gain for less cost than ranibizumab but was not cost-effective compared to bevacizumab ($1,151,451/QALY incremental CUR). The average ophthalmic cost perspective CUR for bevacizumab was $11,033/QALY, $79,600/QALY for ranibizumab, and $44,801/QALY for aflibercept. Eleven-year therapies saved a 1.0 year-of-life loss without treatment from the 11.0-year life expectancy. Early treatment was 138%-149% more cost-effective than late treatment. Two-year therapy prevented a 1-month-of-life loss, and revealed bevacizumab, ranibizumab, and aflibercept conferred 0.141, 0.141, and 0.164 QALY gains, respectively, with corresponding average CURs of $40,371/QALY, $335,726/QALY, and $168,006/QALY, respectively.
From an ophthalmic (medical) cost perspective, bevacizumab, ranibizumab, and aflibercept NVAMD monotherapies were all cost-effective over 11 years, with bevacizumab 6.21× more cost-effective than ranibizumab and 3.06× more cost-effective than aflibercept. Two-year modeling revealed bevacizumab was cost-effective, whereas ranibizumab and aflibercept were not. Early treatment was critical for obtaining optimal vision and cost-effectiveness, as is long-term follow-up and adherence to treatment.
•Bevacizumab, ranibizumab, and aflibercept have similar patient preference-based vision and safety outcomes for treating wet age-related macular degeneration (AMD).•The 3 study VEGF inhibitor therapies are all cost effective over 11 years and prevented loss of life from untreated wet AMD.•Bevacizumab therapy cost effectiveness was found to be 621% greater than ranibizumab therapy and 306% greater than aflibercept therapy.
More than 250 patients with uncomplicated, primary spontaneous pneumothorax were treated conservatively or by pleural intervention. In a complete-case analysis, reexpansion within 8 weeks occurred in ...98.5% of the patients in the intervention group and in 94.4% of those in the conservative-management group.
Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene ...amplification or overexpression has been reported in estrogen receptorpositive (ER⁺) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER⁺ breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxiainducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER⁺/HER2⁻ metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
To perform a societal cost-benefit analysis comparing intravitreal bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eylea) monotherapies for treating neovascular age-related macular ...degeneration (NVAMD).
Cost-benefit analysis.
Center for Value-Based Medicine using published clinical trial and Medicare data. Patient population: 168,400 estimated 2018 U.S. patients with new-onset NVAMD. Procedure(s): cost-benefit analysis using 2018 U.S. real dollars. Outcome measurements: 11-year direct ophthalmic medical costs expended for bevacizumab, ranibizumab, and aflibercept monotherapies were compared with ophthalmic and nonophthalmic direct medical, direct nonmedical, and indirect medical (productivity) costs saved by the therapies.
Bevacizumab monotherapy had an individual, 11-year $14,772 treatment cost and net $357,680 societal return (11-year 2,421% return on investment ROI). Ranibizumab therapy cost $106,582 and returned $265,870 to society (249% ROI), whereas aflibercept treatment cost $61,811 and returned $310,611 to society (503% ROI). The 2018 NVAMD overall treatment cohort, 11-year net societal gain was $28.5 billion to patients and insurers, with $24.2 billion (84.9%) coming from bevacizumab therapy, $0.7 billion (2.5%) from ranibizumab therapy, and $3.6 billion (12.6%) from aflibercept therapy. Substituting bevacizumab for ranibizumab and aflibercept in the 2018 new-onset NVAMD patients would save an estimated $1.343 billion over 11 years. Vascular endothelial growth factor-inhibitor (VEGF-I) therapy in 2018 should contribute $12.2 billion to the Gross Domestic Product over 11 years. Late treatment would decrease this by 78% to $2.7 billion.
Intravitreal NVAMD bevacizumab, ranibizumab and aflibercept monotherapies accrue considerable financial, ROIs to patients and insurers as they increase national wealth.
•For 2018, neovascular age-related macular degeneration (AMD), vascular endothelial-I growth factor inhibitor (VEGF-I) therapy was estimated to return a net $28.5 billion to society (patients and insurers) over 11 years.•2018 VEGF-I therapy was estimated to contribute $12.2 billion to the Gross Domestic Product over 11 years.•Substituting bevacizumab for ranibizumab and aflibercept with neovascular AMD therapy in 2018 would have theoretically saved $1.343 billion in direct ophthalmic medical expenditures.
IMPORTANCE: Select research methods in cost-utility analysis (incremental cost-effectiveness analysis) might potentially bias against patient value (quality-adjusted life-year QALY) gain and ...cost-effectiveness associated with common ophthalmic interventions in disabled, elderly, and African American populations. OBJECTIVE: To ascertain whether using nonpatient vision utilities and/or a maximum limit model constraining vision utility gain to the systemic comorbidity utility level biases against ophthalmic cost-utility outcomes. DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation predominantly used data from the Center for Value-Based Medicine database to perform preference-based comparative effectiveness and cost-utility analyses for cataract surgery and intravitreal ranibizumab therapy for neovascular age-related macular degeneration (NVAMD) using vision utilities acquired from patients with ophthalmic disease (ophthalmic patient utilities) and from surrogate individuals (nonophthalmic patient vision utilities) with and without integrating systemic comorbidity utility limits on vision utility gain. Ophthalmic patient data were collected from January 1, 2000, to December 31, 2016, and analyzed from April 1 to July 1, 2020. INTERVENTIONS: Cost-utility analysis with 3% discount rate in 2018 US dollars. MAIN OUTCOMES AND MEASURES: QALY gains and dollars expended per QALY gain (the cost-utility ratio). RESULTS: A total of 309 participants in the nonophthalmic patient cohort and 505 patients in the ophthalmic patient cohort were included. A reference case of first-eye cataract surgery using ophthalmic patient vision utilities and no systemic comorbidity utility limits yielded a 2.574 (34.2%) QALY gain vs observation. Substituting nonophthalmic patient utilities resulted in a 1.502 (15.5%) QALY gain, whereas using the 0.76 patient systemic comorbidity utility to limit cataract surgery vision utility gain yielded a 1.337 (17.8%) QALY gain. Using both nonophthalmic patient utilities and systemic comorbidity utility limits yielded a 0.839 (8.7%) QALY gain. The substitutions decreased cataract surgery cost-effectiveness by 71.3% (95% CI, 70.6%-72.1%) for nonophthalmic patient utilities, 92.5% (95% CI, 51.9%-133.1%) for patient systemic comorbidity utility, and 206.8% (95% CI, 202.6%-211.2%) for both. The NVAMD ranibizumab therapy reference case yielded a 1.339 (26.1%) QALY gain. Similar substitutions resulted in QALY gains of 1.164 (22.7%) for nonophthalmic patient utilities while reducing cost-effectiveness by 16.4%, 1.001 (19.5%) for systematic-limiting comorbidity utility while reducing cost-effectiveness by 33.8%, and 0.971 (18.9%) for both while reducing cost-effectiveness by 37.9%. CONCLUSIONS AND RELEVANCE: Using nonophthalmic patient vision utilities and/or the maximum limit model of limiting patient utility gains to the population systemic comorbidity utility level resulted in large decreases in patient value (QALY) gain and cost-effectiveness for common ophthalmic interventions. Ophthalmologists should realize these phenomena and consider correcting the potential discrimination against disabled, elderly, and African American populations. This negative potential bias could theoretically result in beneficial intervention denial, less research dollars, curbed therapeutic advances, and decreased interventional reimbursement.
Introduction
Oral administration of zeaxanthin (Zx) 20 mg daily in patients with unilateral neovascular age-related macular degeneration (nAMD) treated with triple therapy (photodynamic ...therapy/intravitreal bevacizumab/intravitreal dexamethasone) reduced fellow-eye 2-year nAMD incidence from 23 to 6% (
p
= 0.02) in a prior clinical trial. We questioned the long-term benefit and thus analyzed case–control 5-year patient data of trial participants and additional participants with 5-year follow-up, also performing cost-utility and cost–benefit analyses.
Methods
Consecutive, unilateral nAMD patient outcomes for those taking 20 mg Zx supplementation orally for ≥ 5 years were compared with the Comparison of AMD Treatments Trials (CATT) 5-year historical controls for fellow-eye nAMD conversion. Eleven-year mean life expectancy, cost-utility and cost–benefit models were undertaken employing a 3% discount rate and 2020 US real dollars.
Results
Among 227 consecutive patients with nAMD/Zx-supplementation, 202 (90%) had 5-year follow-up. The fellow-eye nAMD 5-year conversion incidence using a Kaplan–Meier cumulative event estimate was 22% (49/227), versus 48% (167/348) with CATT control data (
p
< 0.0001). An 11-year cost-utility model with estimates for years 6–11 demonstrated a 0.42 (7.7%) QALY (quality-adjusted life-year) gain, including 3 months of life saved per patient due to decreased nAMD fellow-eye conversion. This yielded a direct ophthalmic medical cost perspective, incremental cost-utility ratio (CUR) of −$576/QALY and a societal cost perspective CUR of −$125,071/QALY. Zx supplementation for all 2020 US unilateral nAMD cases would have theoretically saved society, primarily patients, $6.0 billion over 11 years, a 1531% return on investment (ROI), or 31.3% annual ROI, on Zx costs.
Conclusions
Oral zeaxanthin supplementation for unilateral nAMD patients appears to decrease fellow-eye long-term incidence and is cost-effective and financially rewarding. It is dominant vs. no supplementation in patients presenting with unilateral nAMD.
Trial Registration
ClinicalTrials.gov identifier, NCT01527435.
To assess the incremental, comparative effectiveness (patient value gain) and cost effectiveness (financial value gain) associated with 0.3-mg intravitreal ranibizumab injection therapy versus sham ...therapy for diabetic macular edema (DME).
Value-Based Medicine (Center for Value-Based Medicine, Flourtown, PA) 14-year, cost-utility analysis using patient preferences and 2012 United States real dollars.
Published data from the identical Ranibizumab Injection in Subjects with Clinically Significant Macular Edema with Center Involvement Secondary to Diabetes Mellitus (RISE and RIDE) clinical trials.
An incremental cost-utility analysis was performed using societal and third-party insurer cost perspectives. Costs and outcomes were discounted with net present value analysis at 3% per annum.
The incremental comparative effectiveness was measured in: (1) quality-adjusted life year (QALY) gain and (2) percent patient value (quality-of-life) gain. Cost effectiveness was quantified with the cost-utility ratio (CUR) measured as $/QALY.
The 14-year, incremental patient value gain conferred by intravitreal ranibizumab therapy for diabetic maculopathy was 0.9981 QALY, equating to an 11.6% improvement in quality of life. The direct, ophthalmic medical cost for ranibizumab therapy in 1 eye was $30 116, whereas for 2 eyes it was $56 336. The direct, nonophthalmic, medical costs saved from decreased depression, injury, skilled nursing facility admissions, nursing home admissions, and other vision-associated costs totaled $51 758, resulting in an overall direct medical cost of $4578. The net mean societal cost for bilateral ranibizumab therapy was -$30 807. Of this total, decreased caregiver costs accrued a $31 406 savings against the direct medical costs, whereas decreased wage losses accrued a $3978 savings. The third-party insurer CUR for bilateral ranibizumab therapy was $4587/QALY. The societal cost perspective for bilateral therapy was -$30 807/QALY, indicating that ranibizumab therapy dominated sham therapy because it conferred both a positive QALY gain of 0.9981 and a financial value gain (positive financial return on investment) of $30 807 referent to the direct ophthalmic medical costs expended.
Intravitreal ranibizumab therapy for the treatment of DME confers considerable patient (human) value gain. It also accrues financial value to patients, public and private insurers, and society.
To perform a cost-utility analysis of 2018 United States real dollars for cataract surgery.
Center for Value-Based Medicine, Hilton Head, South Carolina, USA.
Cost-utility analysis.
A base-case ...14-year cost-utility model using the ophthalmic cost perspective was used. Third-party insurer and societal cost perspectives were also analyzed. Patient outcomes and costs were discounted with net present value analysis at 3% a year.
First-eye cataract surgery resulted in a 2.523 quality-adjusted life-year (QALY) gain, a 33.3% patient value gain, and 25.5% quality-of-life gain. Bilateral surgery yielded a 44.1% patient value gain, while second-eye cataract surgery alone conferred an 8.1% value gain. First-eye cataract surgery resulted in a gain of 2.52 QALYs, while second-eye surgery added an incremental gain of 0.81 QALYs. The ophthalmic-cost-perspective average cost-utility ratio was $2526/2.523 = $1001/QALY for first-eye cataract surgery. The societal-cost-perspective average cost-utility ratio was −$370 018/2.523 = −$146 629/QALY. The second-eye ophthalmic-cost-perspective cost-utility ratio was $2526/0.814 = $3101/QALY, while the ophthalmic-cost-perspective cost-utility ratio for bilateral cataract surgery was $5052/3.338 = $1514/QALY. The 14-year U.S. 2018 real-dollar societal-cost-perspective net return on investment for first-eye cataract surgery was $370 018 above the $2526 cost expended for cataract surgery.
Cataract surgery in both the first eye and second eye, when analyzed by standard health economic methodologies, is highly cost-effective. Cataract surgery in 2018 was 73.7% more cost-effective than in 2000.
To assess the conferred value and average cost-utility (cost-effectiveness) for intravitreal ranibizumab used to treat occult/minimally classic subfoveal choroidal neovascularization associated with ...age-related macular degeneration (AMD).
Value-based medicine cost-utility analysis.
MARINA (Minimally Classic/Occult Trial of the Anti-Vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular AMD) Study patients utilizing published primary data.
Reference case, third-party insurer perspective, cost-utility analysis using 2006 United States dollars.
Conferred value in the forms of (1) quality-adjusted life-years (QALYs) and (2) percent improvement in health-related quality of life. Cost-utility is expressed in terms of dollars expended per QALY gained. All outcomes are discounted at a 3% annual rate, as recommended by the Panel on Cost-effectiveness in Health and Medicine. Data are presented for the second-eye model, first-eye model, and combined model.
Twenty-two intravitreal injections of 0.5 mg of ranibizumab administered over a 2-year period confer 1.039 QALYs, or a 15.8% improvement in quality of life for the 12-year period of the second-eye model reference case of occult/minimally classic age-related subfoveal choroidal neovascularization. The reference case treatment cost is $52652, and the cost-utility for the second-eye model is $50691/QALY. The quality-of-life gain from the first-eye model is 6.4% and the cost-utility is $123887, whereas the most clinically simulating combined model yields a quality-of-life gain of 10.4% and cost-utility of $74169.
By conventional standards and the most commonly used second-eye and combined models, intravitreal ranibizumab administered for occult/minimally classic subfoveal choroidal neovascularization is a cost-effective therapy. Ranibizumab treatment confers considerably greater value than other neovascular macular degeneration pharmaceutical therapies that have been studied in randomized clinical trials.
Utilities are preference-based estimates, typically ranging from 1.00 (normal health) to 0.00 (death), that quantify the quality-of-life improvement associated with a health care intervention. In ...conjunction with length-of-life gain, depending on the intervention, they measure total interventional value gain in quality-adjusted life years that can be integrated with costs in cost-utility analysis. We believed it relevant to ascertain whether race was a differentiating factor confounding utilities related to vision.
An analysis of cross-sectional data obtained from consecutive Black and White ophthalmic outpatients from the Wills Eye Hospital (Philadelphia, PA.) practices who participated in a long-standing time trade-off (TTO) vision utility study from 1999 to 2016 was undertaken. Each participant was interviewed by a researcher using a previously validated and reliable TTO vision utility acquisition instrument and assigned to 1 of 5 vision categories according to acuity in the best-seeing eye. Utility outcomes were compared using both the 2-sided t test and the Mann-Whitney U test.
Eleven hundred and twenty-five consecutive patients able to successfully answer the questions were included. For vision of 20/200-20/800, White/Black mean vision utilities were, respectively, 0.58/0.59 (p = 0.84); for vision of 20/70-20/100, they were, respectively, 0.72/0.70 (p = 0.85); for vision of 20/50-20/60, they were, respectively, 0.78/0.79 (p = 0.86); for vision of 20/25-20/50, they were, respectively, 0.84/0.88 (p = 0.16); and for vision of 20/20, they were, respectively, 0.91/0.90 (p = 0.43).
TTO vision utilities in Black and White ophthalmic patient cohorts were alike at various levels of visual acuity. This suggests a similar quality of life and that TTO vision utilities used in cost-utility analysis do not require adjustment for race in Black and White ophthalmic populations in the US.
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