Office Examinations–Directed Treatment Paradigms Reduce Travel Burden, Decrease Treatment Cost, and Improve Quality-Adjusted Life-Years for Patients With Exudative Age-Related Macular Degeneration Undergoing Antivascular Endothelial Growth Factor Therapy

Abstract

Purpose:

In the United States, most intravitreal injections are performed the same day as an office examinations; however, federal agencies and insurance payers suggest these same-day examinations charges are overused and have recommended scrutiny. In this study, we estimate the cost vs benefit to society of same-day office examinations during intravitreal injections for wet age-related macular degeneration (wAMD).

Methods:

An Excel spreadsheet was used to model different antivascular endothelial growth factor treatment scenarios for wAMD, including automatic treatment, injection series' treat and extend (T&E), and as-needed treatment, with increasing same-day examinations in the order listed. Treatment parameters were estimated using US population statistics, published literature, and Centers for Medicare & Medicaid Services, provider utilization data. Costs and benefits were compared for the 4 treatment scenarios.

Results:

Although yearly examinations and optical coherence tomography costs were higher for injection series, T&E, and as-needed protocols compared with automatic treatment, our model predicts reduced yearly injection and travel costs for those same treatment scenarios also, saving $2.9 billion (injection series), $7.2 billion (T&E), and $6.1 billion (as-needed) annually for the US population. Same-day injections accounted for 21%, 8%, and 9% of the savings, respectively, because of reduced travel burden. Furthermore, early detection of wAMD in the fellow eye during office examinations allows for a 1.8, 2.1, and 2.5 quality-adjusted life-year benefit, respectively.

Conclusions:

Office examinations–directed antivascular endothelial growth factor therapy for wAMD reduces travel and treatment expenses and improves screening of the fellow eye, resulting in robust cost savings and quality-adjusted life-year benefit for the US population.

Introduction

Intravitreal injection is the most common ophthalmologic surgical procedure worldwide ¹ and continues to increase in utilization. In the United States, estimates of this procedure have surpassed 5.9 million injections per year ² amid growing reliance on this procedure to treat wet age-related macular degeneration (wAMD) and other retinal conditions. In 2010, there were nearly 2 million Americans with AMD, which is predicted to increase to 3 million and 5 million by 2030 and 2050, respectively. ³ Needless to say, there is increased pressure on the US health care budget resulting from a burgeoning wAMD population treated via repeated intravitreal injections of antivascular endothelial growth factor (anti-VEGF) medication.

In the United States, anti-VEGF injections are commonly administered in the retina clinic the same day as an office visit along with optical coherence tomography (OCT) testing. ⁴ Office evaluation allows assessment and adjustment of ongoing anti-VEGF therapy. Same-day office evaluations also allow monitoring and management of comorbid diseases, screening for AMD in the fellow eye, ^5,6 and reduction of patient trips to the clinic. ⁷ However, examinations and OCT testing carry additional cost and prolong the visit for the patient. Furthermore, the US Department of Health and Human Services Office of Inspector General has suggested that modifier 25 (Current Procedural Terminology used to report an evaluation and management service on the same day as a minor procedure by the same physician) is overused, ⁸ implying that clinics should perform fewer same-day examinations and/or bill less for these services.

Thus, there is controversy regarding the cost vs benefit to society of same-day office examinations. The purpose of this study is to determine the economic impact of same-day office examinations during anti-VEGF injections in the treatment of wAMD.

Methods

For this study, we have modeled the expenses related to anti-VEGF therapy for wAMD over a 1-year period for a single patient and for the US population as a whole. Treatment parameters are based on available data from previously published literature and provider utilization and cost figures from the Centers for Medicare & Medicaid Services (CMS). Annual costs and savings are calculated using Microsoft Excel (version 16.29.1).

Treatment Protocols

Our study explores 4 established treatment protocols that use different proportions of same-day office examinations (Table 1). The first protocol, automatic treatment, is modeled after clinical trials, including Minimally classic/occult trial of the anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD (MARINA), ⁹ ANti-VEGF antibody for the treatment of predominantly classic CHORoidal neovascularization in AMD (ANCHOR), ¹⁰ the Comparison of Age-related macular degeneration Treatments Trials (CATT), ¹¹ Vascular endothelial growth factor trap-eye: Investigation of Efficacy and safety in Wet age-related macular degeneration (VIEW) 1/2, ¹² and pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR), ¹³ as well as the package inserts for aflibercept and ranibizumab. Automatic treatment uses the minimum number of examinations (2 per year). The second protocol, injection series, is described by the Mayo Clinic. ^14,15 For patients in the injection series group, a same-day exams with OCT testing determines a set number of injection-only visits that take place over a cycle. After that cycle, a new evaluation and OCT determine parameters for the next cycle. Limited screening is performed during the injection-only visits and complete evaluations occur at the beginning of each cycle.

Table 1.

Treatment Parameters for US Patients With Wet Age-Related Macular Degeneration (Annual).

Parameter	Annual No.	Sourcea
Automatic treatment protocol
Injection treatments	10.1	Windsor et al (2018) 18
Examinations (separate day)	1.9	Curtis (2012) 19
OCTs	1.9	Assumption
Injection series (with examinations visits at beginning of each cycle)
Injection treatments	8.6	Atchison et al (2017)15
Same-day examinations visits	4.7	Atchison et al (2017) 15
Noninjection examinations visits	0.0	Atchison et al (2017) 15
OCTs	4.7	Assumption
Treat and extend protocol
Injection treatments	5.8	Windsor et al (2018) 18
Same-day examinations visits	5.8	Windsor et al (2018) 18
Noninjection visits	0.0	Assumption
OCTs	5.8	Windsor et al (2018) 18
As-needed protocol
Injection treatments	5.4	Martin et al (2012) 11
Same-day examinations visits	5.4	Martin et al (2012) 11
Noninjection examinations visits	6.1	Martin et al (2012) 11
OCTs	11.5	Martin et al (2012) 11

Abbreviation: OCT, optical coherence tomography.

^a Annual rates were calculated from Atchison et al ¹⁵ assuming steady enrollment over the 4-year study period.

The third protocol, treat & extend (T&E), is well described, ^16,17 and according to member surveys by the American Society of Retina Specialists (ASRS), is the most common protocol currently practiced. ⁴ In T&E, office evaluation and OCT testing are performed to assess response to treatment and determine the treatment interval for the next dose. In general, T&E allows the treatment interval to be adjusted after each visit, depending on the course of the patient’s individual disease. The fourth protocol, as-needed treatment was described previously ¹¹ and is used in current practice, although less commonly so compared with T&E. In as-needed treatment, the patient is evaluated with examinations and OCT testing each month and undergoes anti-VEGF intravitreal injection depending on whether the exams and testing shows active AMD disease.

In all 4 treatment protocols, examinations and OCTs are assumed to evaluate both the treated eye and the fellow eye; this is consistent with practice guidelines ^{20 -22} for monitoring dry AMD in the fellow eye for the purpose of early detection and treatment of wAMD. We further assumed the occurrence of these visits on the same day as an injection because patients generally prefer this as opposed to examinations and treatment on separate days. ⁷ However, some retina specialists schedule exams and injections on separate days to avoid controversy related to modifier-25 examinations codes, and so calculations were repeated for separate-day injections to estimate the impact on cost of same-day vs separate-day injections. It is likely that comorbid eye conditions such as dry AMD, diabetic retinopathy, posterior vitreous detachment, dry eye syndrome, and other conditions⁶ are screened, monitored, and managed during examinations visits; however, for the purpose of this model, we considered the screening of dry AMD in the fellow eye but we did not consider the screening of other conditions despite the obvious benefit to the patients.

Cost Estimates

Cost estimates for office examinations, OCT, injection, and medication reflect Medicare-allowed amounts reported on the 2017 CMS Provider Utilization Data webpage. ²³ The average cost of an anti-VEGF medication (Supplemental Table 1) was calculated as the weighted average of agents in current use. ¹⁸ Travel cost was estimated based on the average round-trip distance from home to clinic for a cohort of patients undergoing intravitreal injections at a retina clinic⁶ and the standard mileage reimbursement rate listed on the Internal Revenue Service webpage. ²⁴ Patients were assumed to have a chaperone with them for clinic visits and injection-only visits, ⁷ and chaperone time was estimated using reported clinic and travel times ²⁵ and average hourly wage reported on the Bureau of Labor Statistics webpage. ²⁶

Demographics of the US Population With wAMD

There are approximately 2.5 million patients in the US with wAMD, ^{27 -29} and for the purposes of this model, we assume that 60% of them are actively treated with anti-VEGF therapy. ^2,30

Model of AMD in the Fellow Eye

Our model assumes that 6% of patients with wAMD develop wAMD in the fellow eye per year. ^5,6 Transition of dry to wAMD in the fellow eye can happen at any time during the course of treatment; our model assumes that the transition of the fellow eye occurs halfway between examinations, and that visual acuity (VA) begins to decline at the time of transition, which follows a natural history curve based on the literature, ^31,32 until disease is detected at the next examinations. We assume treatment is initiated at the visit when wAMD is detected, and we further assume that VA begins to improve at that time (Figure 1), which is parallel to a treatment curve for vision gain that is an average of multiple clinical trials. ^{9 -13,17} Our model assumes a similar response in VA for all 4 protocols after the treatment begins.

Figure 1.

Model for visual acuity in the fellow eye on transition from dry to wet age-related macular degeneration, depending on the delay between transition and detection. The model is based on the natural history of untreated wet age-related macular degeneration (closed circles, “no treatment”) ^31,32 and the visual acuity response to treatment (open circles, “no delay”), which comes from an average of MARINA, ⁹ ANCHOR, ¹⁰ CATT, ³³ VIEW 1 and 2, ¹² HARBOR, ¹³ and TREX ¹⁷ clinical trial results. For our model, vision loss follows the natural history curve until detection and initiation of fellow eye treatment, at which point vision improves in parallel to the “no delay” treatment curve, albeit starting later and from a lower point, depending on whether detection was delayed by 1.0 month (treat and extend [T&E] protocol), 0.52 months (as-needed [PRN] protocol), 1.2 months (injection series protocol), or 3.2 months (automatic treatment protocol). The area under these curves was used to compute utility and quality-adjusted life-years.

Quality-Adjusted Life-Years and Incremental Cost-Effectiveness Ratio of Early Detection of wAMD in the Fellow Eye

Quality-adjusted life-years (QALYs) is calculated using the method of Brown et al ³⁴ and the Czoski-Murray utility algorithm for VA in the better-seeing eye. ^35,36 In brief, the model converts VA to utility (quality of life) using the Czoski-Murray formula:

$$\text{Utility}=0.860-0.368\times \left(\text{Visual} \text{Acuity} \text{LogMAR}\right)-0.001\times \left(\text{Patient Age}\right)$$

where logMAR is the logarithm of the minimum angle of resolution.

Utility is calculated for each month during the 1-year period that follows conversion from dry AMD to wAMD. The model assumes an age of 68.6 years when the fellow eye transitions to wAMD, ⁵ a life expectancy of 78.5 years, ³⁷ and stable VA as treatment continues beyond 1 year. The model further assumes that changes in VA do not affect life expectancy. QALY is then calculated as the area under the utility curve and compared for the various protocols in this study.

The incremental cost-effectiveness ratio (ICER) was calculated from the formula:

$$\text{ICER }=\frac{\left(\text{Difference} \text{in} \text{Cost}\right)}{\left(\text{Difference} \text{in} \text{QALY}\right)}$$

where cost includes the cost of screening the population with examinations and OCT testing, as well as the cost of early treatment when fellow-eye wAMD is detected early. The parameters and calculations of QALY and ICER are further detailed in Supplemental Table 2.

Results

The annual cost of examinations and OCT testing was higher for the injection series, T&E, and as-needed protocols, as compared with automatic treatment, for individual patients (Figure 2) and for the wAMD population in the United States as a whole (Table 2). However, our model predicts a lower treatment cost (Figure 3 and Table 3) for the injection series, T&E, and as-needed protocols.

Figure 2.

The annual per-patient cost of examinations and optical coherence tomography testing concurrent with automatic treatment, injection series, treat and extend (T&E), and as-needed (PRN) protocols for wet age-related macular degeneration are shown. Note the increasing proportion of examinations and optical coherence tomography testing with these 4 treatment paradigms in the order listed. Annual costs are estimated and shown for individual patients; for the US population as a whole, see Table 2.

Table 2.

Annual Cost of Examinations and Optical Coherence Tomography (OCT) Testing for Patients With Wet Age-Related Macular Degeneration.^a

	Per patient, $	US population, $
Automatic treatment
Exams (1.9)	201	301,202,250
OCTs (1.9)	79	118,189,500
Annual cost	280	419,391,750
Injection series
Exams (3.38)	357	535,764,236
OCTs (3.38)	140	210,252,900
Annual cost	497	746,017,136
Treat and extend
Exams (5.8)	616	924,056,798
OCTs (5.8)	242	362,592,945
Annual cost	858	1,286,649,743
As-needed
Exams (11.45)	1210	1,815,139,875
OCTs (11.45)	475	712,247,250
Annual cost	1685	2,527,387,125

^aNumber in parenthesis is the number of occurrences per year.

Figure 3.

Annual per-patient cost of injections and drugs for treatment of wet age-related macular degeneration. The cost of drugs associated with wet age-related macular degeneration therapy represents the largest cost of treatment (compared with examinations, testing, travel, and chaperone costs). Note the decreasing drug costs for treatment paradigms in the order listed, owing to more personalization of treatment (with fewer injections for patients who need less). Annual costs are estimated and shown for an individual patient; for the US population as a whole, see Table 3. T&E, treat and extend; PRN, as-needed.

Table 3.

Annual Cost of Injections and Drugs for Treatment of Wet Age-Related Macular Degeneration.^a

	Per patient, $	US population, $
Automatic treatment
Injections (10.1)	1189	1,784,008,800
Drug (10.1)	10,671	16,006,402,440
Annual cost	11,860	17,790,411,240
Injection series
Injections (8.6)	1016	1,523,949,078
Drug (8.6)	9115	13,673,106,458
Annual cost	10,131	15,197,055,536
Treat and extend
Injections (5.8)	688	1,031,645,565
Drug (5.8)	6171	9,256,083,316
Annual cost	6858	10,287,728,881
As-needed
Injections (5.5)	637	955,719,000
Drugs (5.5)	5717	8,574,858,450
Annual cost	6354	9,530,577,450

^aNumber in parenthesis is the number of occurrences per year.

The T&E protocol had the lowest travel and chaperone costs (Figure 4) because more frequent examinations allowed treatments to be spaced out further. However, this benefit was reduced when examinations and injections were performed on separate days. Travel and chaperone costs were higher by 24% (automatic treatment), 57% (injection series), 73% (T&E), and 37% (as-needed) compared with same-day injections because of extra trips back and forth for the patient and his or her chaperone. Even though the travel and chaperone costs are relatively small compared with medication cost, the increase in total cost was still considerable: 2.9% (automatic treatment), 21% (injection series), 8.4% (T&E), and 9.5% (as-needed) when the model was constrained to separate-day injections.

Figure 4.

Annual per-patient cost of travel and chaperone time for treatment of wet age-related macular degeneration. The cost of travel to the clinic accompanied by a driver or chaperone is shown for each protocol. The filled bars denote cost assuming injection visits and examinations visits are combined the same day when possible; open bars denote additional cost of returning a separate day for the injection. The injection series and treat and extend (T&E) protocols are associated with less-expensive travel and chaperone costs (owing to fewer visits to clinic) for same-day injections, and separate-day injections add significantly to travel and chaperone cost for all protocols. Travel and chaperone costs are shown here for an individual patient; for the US population as a whole, see Table 4. PRN, as-needed.

Table 4.

Cost of Travel and Chaperone Time for Treatment of wAMD (Annual, US Population) With Examinations and Injection Administered the Same Day vs a Separate Day.

	Same-day injections, $	Separate-day injections, $
Automatic treatment
Mileagea (470 vs 558 mi)	407,786,400	484,650,900
Chaperone timeb (1308 vs 1487 min)	733,063,080	928,531,580
Annual cost	1,140,849,480	1,413,182,480
Injection series
Mileagea (402 vs 617 mi)	349,960,489	536,862,589
Chaperone timeb (1053 vs 1669 min)	657,598,500	1,042,290,500
Annual cost	1,007,558,989	1,579,153,089
Treat and extend
Mileagea (542 mi)	235,812,195	471,624,390
Chaperone timeb (1467 min)	567,872,838	916,141,500
Annual cost	803,685,033	1,387,765,890
As-needed
Mileagea (784 mi)	463,209,750	681,666,750
Chaperone timeb (2159 min)	1,017,248,050	1,348,295,500
Annual cost	1,480,457,800	2,029,962,250

Abbreviations: mi, miles; wAMD, wet age-related macular degeneration.

Annual total per patient mileage and chaperone time are listed (for examinations and injection visits on the same vs separate days).

^a Miles reimbursed at a rate of $0.58/mi per US Internal Revenue Service (2019). ²⁴

^b Time reimbursed at average US wage ($24.98/h) per Bureau of Labor Statistics (2019). ²⁶

Our model predicts an annual total cost of treatment (including examinations, OCT testing, injection, and travel/chaperone costs) for the wAMD population in the United States of $20 billion for automatic treatment, $17 billion for injection series, $12 billion for T&E, and $14 billion for as-needed treatment. Thus, there is substantial total savings in personalizing each patient’s wAMD treatment.

Furthermore, there is also improved QALYs, as compared with automatic treatment, owing to early detection and treatment of wAMD in the fellow eye, totaling 1.8, 2.1, and 2.5 QALYs per patient who converts from dry AMD to wAMD in the fellow eye for injection series, T&E, and as-needed protocols, respectively. The ICER of monitoring the fellow eye in the US population was $2663, $5170, and $9789 for the injection series, T&E, and as-needed protocols, respectively.

Conclusions

This model compares the cost and QALYs for 4 anti-VEGF treatment protocols for wAMD: automatic treatment, injection series, T&E, and as-needed treatment. The 4 protocols vary in frequency of concurrent office examinations (in increasing frequency as listed), and with more frequent examinations the latter protocols are able to personalize treatment, thereby saving travel costs, total costs, and vision in the fellow eye.

CMS and private insurers have suggested that modifier-25 same-day examinations are overused by ophthalmologists and other practitioners and deserve scrutiny. ^8,38 Anti-VEGF therapy of wAMD in particular is accompanied by frequent same-day modifier-25 visits in current practice in the United States, where the T&E protocol is most frequently used ⁴ ; therefore, there is much interest in whether reducing examinations might control the cost of wAMD therapy. In fact, our model predicts the opposite: Total cost is higher when examinations and injections are performed on separate days. Furthermore, total costs are highest when treatment is automatically administered (according to the package insert) without periodic exams to guide treatment.

Besides the cost savings predicted by our model, same-day visits can also aid early detection and treatment of other retinal conditions such as diabetic retinopathy, posterior vitreous detachment, and epiretinal membrane ⁶ ; allow screening for nonretinal ocular diseases such as cataract, glaucoma, infections, blepharitis, and dry eye syndrome; detect other medical conditions such as hypertension, cholesterol plaques, and smoking; reduce indirect costs such as missed work; and simplify travel for elderly or disabled patients. ²⁵ These benefits of same-day examinations are acknowledged but do not factor into the calculations of this model.

There is some controversy about which protocol is best in terms of VA outcomes, but for this model we assume that the T&E protocol is noninferior to automatic treatment based on the findings of the TReat and EXtend (TREX) Study Group. ¹⁷ A limitation of the present study is that it does not account for undertreatment of wAMD, which can occur with fewer visits per year, scheduling difficulties, or patient noncompliance that can happen in any of the protocols. Theoretically, patient compliance might improve with fewer total visits, whereas undertreatment might improve with more frequent injections.

Another limitation of the study is that it does not account for bilateral injections in patients with bilateral wAMD. For these patients, screening of the fellow eye for a transition from dry to wAMD is irrelevant. However, screening of both eyes for other eye disease and systemic disease is still an important and beneficial service to patients.

Automatic treatment can save on examinations and OCT costs, as compared with injection series, T&E, or as-needed protocols (see Figure 2). However, the extra cost of exams and OCT testing is small compared with the medication cost savings and QALY improvements for patients. Considering the cost of screening patients and the cost of early treatment, we calculate a cost-per-QALY (ICER) of less than $10,000 regardless of whether injection series, T&E, or as-needed protocol is used, which is a highly favorable ICER as compared with other accepted medical treatments. ³⁹

In summary, our model compares the costs of anti-VEGF therapy for automatic treatment vs treatment protocols that use examinations to guide individual treatment. All 3 examinations-directed treatment paradigms resulted in cost savings per patient and for the US population as compared with automatic treatment. Our model finds that complete examinations of both eyes with OCT testing can reduce travel and treatment costs and improve screening of the fellow eye, resulting in robust cost savings and QALY benefit for the US population. We conclude that same-day examinations are a valuable component of anti-VEGF therapy in the treatment of wAMD because they allow personalization of the treatment regimen, reduce travel burden, and save on treatment costs.