Vision: 2-Year Analysis

According to clinical trials, ^{, , ,} meta-analyses, ^, Cochrane Database Systematic Reviews, ^, a U.S. database, and a large IRIS registry study, the vision results of the 3 drugs under study were the same through the 24 months of randomized clinical trial data.

Vision: 11-Year Analysis

There were statistical differences at 2 years after baseline between the CATT drug cohorts that received monthly injections versus as-needed injections. Combining the ranibizumab and bevacizumab cohorts, there was a 24-month, 2.4 greater letter gain with monthly injections than with the as-needed injections ( P = .046). The present authors therefore modeled the more visually favorable monthly injection regimen for bevacizumab and ranibizumab during the first 24 months after baseline treatment. Because it was noted in the VIEW trials that bimonthly aflibercept injections yielded vision outcomes equivalent to monthly aflibercept and ranibizumab injection results after 3 initial monthly injections, our study modeled half the administration frequency for aflibercept versus ranibizumab and bevacizumab after the first 24 months ( Supplemental Table 2 ). ^{, , ,}

For months 25-60 for ranibizumab and bevacizumab, vision results were modeled after the 5-year CATT study results, which were very similar to those of the HORIZON trial, an open-label extension of ranibizumab for the treatment of NVAMD, and the 5-year follow-up, Australian retrospective review. Averaging these results resulted in a 5-year outcome of 20/63-1.

The authors assumed that, during this period, aflibercept was administered with half the frequency of ranibizumab and bevacizumab. Table 1 shows the vision treatment results, their evidence-based vision basis, and the untreated control cohort vision results. ^,

From months 61-88 (years 5-7.4), vision results were modeled after the SEVEN-UP (post-MARINA/ANCHOR and HORIZON trials) study for all 3 drugs. It should be noted that the authors biased against more favorable SEVEN-UP vision results by integrating data from the top 2 sub-cohort vision outcomes rather than just the top cohort of 11 or more injections; the latter was used to model VEGF-inhibitor-treated subjects in our cost-utility analysis. This amalgamation resulted in a letter loss of 0.6 from the end of year 5 to year 11, with a resultant vision of 20/63-2 during that time. From months 89-132, we used a last-observation-carried-forward model from the SEVEN-UP vision results at 88 months (7.4 years). Months 61-132 were modeled with the 10-year treatment described in the study by Suner and associates, with vision outcomes identical to those in SEVEN-UP through 88 months.

After 5 years, the authors arbitrarily assumed that bevacizumab and ranibizumab were administered 3 times a year from years 6 to 8 and twice yearly from years 9 to 11 ( Supplemental Table 2 ). Thus, 11 bevacizumab and ranibizumab injections were given after 4 years, the minimum number needed in SEVEN-UP to obtain the best visual result. Aflibercept injections from years 3 to 11 were given half as often as ranibizumab and bevacizumab.

Control Cohort

For controls, the authors used 2-year, MARINA, and ANCHOR sham-treatment, ranibizumab trial data for the 2-year analysis, ^, followed by a Shah and Del Priore Lineweaver-Burke plot meta-analysis of the natural history of untreated NVAMD for years 3 to 11 in the 11-year analysis. Shah and Del Priore integrated the untreated control cohort vision results from 6 previous, randomized clinical trials. Those authors found that mean vision in a cohort correlates highly with the time since the development of NVAMD. The visual acuities at specific times are shown in Table 1 .

Cost-Utility Analysis

The reference case herein was based primarily upon the ophthalmic cost perspective cost-utility ratio (CUR) which was calculated by dividing the ophthalmic direct medical costs expended for an intervention by the quality-adjusted life-years (QALYs) gained. The cost-utility methodology was similar to that used in other value-based medicine ophthalmic cost-utility analyses using patient utilities, an average national Medicare Fee Schedule, and a 3% annual discount rate for QALY outcomes and costs (the last recommended by the Second Panel on Cost-Effectiveness in Health and Medicine ). The time tradeoff utilities were obtained from a visual utility database of 1,400 ophthalmic patient interviews. The utilities have been validated, are reproducible, correlated most highly with vision in the better-seeing eye, and are typically unaffected by comorbidities, sex, age, ethnicity, and Western country of origin. They are generally, but not always, unaffected by the underlying cause of vision loss. ^,

The authors also integrated newer data for vision-related mortality into the current analysis (see Mortality below).

A combined-eye model cost basis was used. ^{, , ,} This model included a weighted average of first-eye and second-eye models. ^{, ,} The second-eye model assumes that the first eye already has vision loss from NVAMD or another cause. Thus, patient value gain begins immediately at the time of initiation of therapy in the second eye.

With the first-eye model, it is assumed that the fellow eye has good vision. We have been unable to demonstrate a significant improvement in quality-of-life (QOL) when vision improves in 1 eye (e.g., 20/200 to 20/63 or 20/63 to 20/40) and the fellow eye has normal vision. ^, In that instance, QALYs are gained when the second eye with good vision eventually converts to NVAMD and is treated. The authors have modeled using CATT data showing that 60% of cases at baseline underwent second-eye treatment (second-eye model) and that 40% had the first eye treated (first-eye model), with good vision at baseline in the fellow eye. With the first-eye model, fellow eyes were treated if they converted from atrophic AMD to NVAMD over the 2- or 11-year model ( Table 2 ). With the first-eye model, QALY gains were assumed to occur only when second eyes were treated for conversion for NVAMD and experienced decreased vision.

The authors did not use a methodology that has been noted by some that decreases the interventional utility gain in individuals who are elderly or have disabilities, thus biasing against these groups. That methodology has little chance of becoming public policy in the United States.

Using the ophthalmic cost perspective, the direct ophthalmic costs expended typically result in a positive CUR because the ophthalmic direct medical costs expended generally exceed ophthalmic direct medical costs saved (e.g., low-vision costs). Use of a societal cost perspective more commonly has a negative CUR because the direct ophthalmic medical costs expended are much more likely to be exceeded by the costs saved (caregiver costs, medical costs such as trauma and depression, wage loss prevented, and others). Thus, the overall costs associated with the intervention are negative. A negative CUR can also be encountered when one intervention dominates another, meaning that it delivers greater QALY gain for less cost than the comparator intervention.

Patient Value

Improvement in QALY and/or Length of Life Gains: Mean vision measurements in the VEGF-I cohorts and control cohorts each year were converted to utility format, ranging from a utility of 0.80 for 20/40 vision in the better-seeing eye to 0.538 associated with 20/630 vision, to calculate the yearly QALY accrual associated with therapy versus none ( Table 3 ). ^, The QALY loss from adverse events was subtracted from the total QALY accrual in each treated eye. Adverse events included cases of endophthalmitis per 1,756 intravitreal injections, ^, 1 day of post-injection ocular discomfort (utility = 0.89) and 2 days of post-injection ocular erythema (utility = 0.96). The 11-year QALY loss from adverse events was 0.070 QALY per eye in the bevacizumab and ranibizumab cohorts and 0.035 QALY per eye in the aflibercept cohort receiving fewer intravitreal injections. For the 2-year model, the respective adverse event QALY losses were 0.065 per eye and 0.032 per eye. Systemic adverse events, such as death and cardiovascular events, were not considered due to the similar incidence rates among the 3 drugs and the uncertainty as to whether they exceeded those found in an age-matched population without NVAMD. ^{, ,}

Mortality

Christ and associates calculated the risk of premature death associated with vision loss in the better-seeing eye ( Supplemental Table 3 ). Their comprehensive methodology and statistical analysis are well described in a study of 2,520 ophthalmic patients with baseline ages of 65-84 years and 20-year follow-up in the Salisbury Eye Evaluation Study. Referent to 20/20 vision with a hazard ratio of 1.0 for the chance of dying within 8 years, the hazard ratio for 20/40 vision was 1.03, 1.08 for 20/80, and 1.18 for 20/200. The calculation by Christ and associates in our present study demonstrated that, for 20/630 vision, the hazard ratio was 1.33. Thus, there is a 33% higher chance that someone with 20/630 vision will die within 8 years than a person with 20/20 vision. When the annual mean vision changes between the present cohorts treated with VEGF-I and those of the control cohort were analyzed ( Table 1 ) and correlated with the hazard ratios, the mean treated patient in each of the bevacizumab, ranibizumab, and aflibercept cohorts had a life expectancy of 11.0 years, whereas the mean person in the untreated control cohort was calculated to have a mean life expectancy of 10.0 years. Thus, VEGF-inhibitor monotherapy resulted in the prevention of approximately 1.0 year of life lost for the average untreated NVAMD patient, a 0.259 QALY gain for bevacizumab and ranibizumab and a 0.266 QALY gain for aflibercept, each consisting of 19.2% of the total QALY gains, respectively, of 1.339 and 1.380, respectively. In the 2-year model, VEGF-inhibitor therapy prevented 1 month of life loss over 2 years while gaining 8.1% of the total bevacizumab and ranibizumab QALY gains and 6.6% of the QALY gain associated with aflibercept therapy.

Costs

The ophthalmic direct medical costs (paid by insurers and patient out-of-pocket dollars) were taken directly from the 2018 national average Medicare fee schedule ( Table 4 ). Although only 1 eye was enrolled in the clinical trials studied, the authors also included the costs associated with treating fellow eyes with atrophic AMD (age-related macular degeneration) that converted to NVAMD with the same drug during the 11-year ( Table 5 ) and 2-year ( Table 6 ) models to simulate clinical practice. The direct nonophthalmic medical costs were taken from a study by Javitt and associates, and the direct nonmedical costs (caregiver costs) were taken from a study by Brown and associates, and the indirect medical costs were taken from Brown and associates, The U.S. Bureau of Labor Statistics, and the Household Economic Studies from the US Census Bureau. Direct nonmedical, or caregiver, costs included 27% for paid caregivers and 73% for unpaid caregivers, similar to what has been noted by others.

Table 4

Eleven-Year and Two-Year Direct Ophthalmic Medical Costs Per VEGF-I Monotherapy-Treated Baseline Patient in 2018 U.S. Real Dollars

National Average Medicare Fee Schedule Costs
Entity (2018 U.S. Nominal $ Cost per 1 Service)	Medicare HCPSC #	Bevacizumab (1.25 mg/Dose)	Ranibizumab (0.5 mg/dose)	Aflibercept (2.0 mg/Dose)
Initial eye examination ($154)	92,004	$154	$154	$154
Office examination ($129)	92,014	$2,066	$2,066	$6,226
Optical coherence tomography ($42)	92,134	$2,593	$2,593	$2,593
Fundus photographs ($58)	92,250	$114	$114	$114
Fluorescein angiography ($88)	92,235	$173	$173	$173
Intravitreal injection ($104)	67,028	$4,879	$4,879	$2,423
Drug ASP cost a	See below	$3,717	$87,727	$45,005
Adverse events	NA	$11	$11	$6
Bevacizumab	J9035	$789	–	–
Ranibizumab	J2778	–	$1,870	–
Aflibercept	J0178	–	–	$1,936
Eleven-year model
Total cost per treated baseline eye	NA	$13,565	$97,573	$56,546
Direct ophthalmic medical cost per fellow eye converting to NVAMD	NA	$1,207	$9,009	$5,266
Total direct ophthalmic medical cost per average patient	NA	$14,772	$106,582	$61,811
Bilateral drug cost/direct ophthalmic medical cost per average patient	NA	27.4%	89.7%	79.3%
Two-year model
Total cost per treated second-eye model eye	NA	$5,526	$45,961	$25,584
Direct ophthalmic medical cost per fellow eye converting to NVAMD	NA	$410	$3,395	$1,972
Total direct ophthalmic medical cost per treated first-eye model eye patient	NA	$5,937	$49,356	$27,557
Total direct ophthalmic medical cost per weighted average of first-eye model eye (40%) and second-eye model eyes (60%)	NA	$5,690	$47,319	$26,377

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