Trends in AntiVascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013

Abstract

Purpose: To analyze antivascular endothelial growth factor (anti-VEGF) injection trends for Medicare Part B beneficiaries during the period 2013–2021, as well as before and after step therapy implementation. Methods: This study examined ophthalmologists administering intravitreal anti-VEGF injections to Medicare Part B beneficiaries from January 1, 2013 through December 31, 2021. Data were gathered from the Medicare Physician & Other Practitioners - by Provider and Service database and identified using Current Procedural Terminology codes specific to bevacizumab, ranibizumab, and aflibercept. Statistical analyses were conducted using R. Results: Among 26 602 816 total injections performed from 2013 to 2021, relative usage of aflibercept increased by 158.3%, while relative usage decreased by 27.5% for ranibizumab and 49.6% for bevacizumab. After step therapy implementation, relative usage of aflibercept increased by 32.0%, while there was a decrease in relative usage of bevacizumab by 33.2% and ranibizumab by 4.3%. When ophthalmologists were grouped according injection volume for each medication in 2021 (ie, top 10%, or high-volume injectors), the proportion of aflibercept injections performed by high-volume aflibercept injectors (32.3% of total nationwide aflibercept injections) was lower than the proportion of ranibizumab injections performed by high-volume ranibizumab injectors (43.2% of total nationwide ranibizumab injections) and the proportion of bevacizumab injections performed by high-volume bevacizumab injectors (41.2% of total nationwide bevacizumab injections). Ranibizumab was less frequently used than aflibercept or bevacizumab. Ophthalmologists in the study time period primarily treated patients with aflibercept and bevacizumab or aflibercept and ranibizumab, with many fewer using primarily ranibizumab and bevacizumab. Conclusions: Aflibercept usage has continued to rise, matched by a decline in bevacizumab usage and a modest decrease in ranibizumab usage. Step therapy has not significantly increased bevacizumab usage on an aggregate level.

Keywords

anti-VEGF agents injections Medicare step therapy retina

Introduction

Vascular endothelial growth factor (VEGF) is a mediator of retinal and choroidal neovascularization, and anti-VEGF agents have been widely adopted to treat a growing number of ocular diseases.^1–8 The 3 major anti-VEGF agents used in ophthalmology are aflibercept (Eylea; Regeneron), ranibizumab (Lucentis; Genentech), and bevacizumab (Avastin; Genentech). Bevacizumab was initially approved for treating colon cancer and was subsequently demonstrated to be effective in treating neovascular age-related macular degeneration (AMD).^9–13 The use of bevacizumab for treating ocular conditions is off-label. Ranibizumab is an antiangiogenic monoclonal antibody fragment that is approved by the US Food and Drug Administration (FDA) for treating neovascular AMD, macular edema after retinal vein occlusions (RVOs), myopic choroidal neovascularization (CNV), diabetic macular edema (DME), and diabetic retinopathy.^14–22 Aflibercept was approved by the FDA in 2011 for treating AMD, macular edema after RVOs, DME, and diabetic retinopathy.^23–26

Studies have demonstrated that these 3 anti-VEGF agents exhibit similar effectiveness. In the case of neovascular AMD, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) showed that monthly bevacizumab injections resulted in noninferior visual acuity gains when compared with monthly ranibizumab, but it also found that ranibizumab demonstrated a greater decrease in central retina thickness than did bevacizumab.²⁷ Other studies have further supported the idea that bevacizumab, ranibizumab, and aflibercept are effective for achieving visual acuity gains in patients with neovascular AMD. However, similar to the observations from the CATT trials, studies have found other FDA-approved drugs to be superior to bevacizumab with respect to anatomic outcomes.^28,29

Outside of neovascular AMD, some studies have found differences in effectiveness for treating DME. The Diabetic Retinopathy Clinical Research Network (DRCR) Retina Network Protocol T showed that aflibercept is superior to bevacizumab and ranibizumab after 1 or 2 years of treatment for patients who had initial visual acuity of 20/50 or worse.³⁰ However, there were no differences in mean change in visual acuity at 1 or 2 years among patients with better baseline visual acuity.³¹ Visual acuity gains for patients with RVOs have also been found to be similar between the 3 agents in some studies, while other studies have found bevacizumab to fail to demonstrate noninferiority to ranibizumab when treating RVOs.^32–34

In addition, DRCR Retina Network Protocol AC examined step therapy by comparing initial bevacizumab treatment with a switch to aflibercept only if certain criteria for improvement were not met, versus immediately starting aflibercept in eyes with visual acuity of 20/50 or worse. Protocol AC found no significant difference in visual outcomes between the different treatment algorithms, despite a large percentage of patients (70%) being switched to aflibercept within the 2-year study period.³⁵

Bevacizumab, ranibizumab, and aflibercept differ greatly in cost. Using 2015 wholesale acquisition costs, a 2.0 mg dose of aflibercept costs $1,850 and a 0.3 mg dose of ranibizumab costs $1,170, while a 1.25 mg dose of bevacizumab costs approximately $60.³⁶ Given the significant cost differences between these agents, there has been much debate in the ophthalmology community regarding the balance between cost-containment and medication selection for managing retinal diseases. In 2019, the Centers for Medicare & Medicaid Services (CMS) began allowing Medicare Advantage plans to implement step therapy for Part B drugs.³⁷ Notably, this policy only applies to Medicare Advantage plans, and Medicare Part B beneficiaries are not subject to fail-first therapy. Step therapy is a fail-first approach that requires demonstration of failure of bevacizumab treatment prior to initiating a switch to the more expensive ranibizumab or aflibercept. The definition of treatment failure is not always well defined and varies by ophthalmologist, but generally it is considered to be an inadequate treatment response or continued vision loss that may be accompanied by clinical biomarkers indicative of disease progression, which can vary based on the disease in question.³⁸ Step therapy has had uncertain implications on practitioner use patterns and supply chain considerations.³⁷

The goal of this research study was to analyze nationwide trends in anti-VEGF injection usage, specifically examining the use of different anti-VEGF agents and how step therapy policies may have impacted these trends over time. We hypothesized that step therapy policies would result in increased use of bevacizumab over aflibercept and ranibizumab over the study period. However, we also considered that among patients who are being treated through step therapy, the volume of bevacizumab may ultimately decrease due to eventual switching to branded drugs.

Methods

The study did not involve human subjects, and the data for this study were obtained from a publicly available database and did not contain personally identifiable information. As such, informed consent and institutional review board approval were not required.

Intravitreal anti-VEGF injection data from January 1, 2013 through December 31, 2021 were gathered from the publicly available Medicare Physician & Other Practitioners - by Provider and Service database.³⁹ This database contains information on services and procedures provided to Original Medicare (fee-for-service) Part B (Medical Insurance) beneficiaries by physicians and other healthcare professionals, and it does not include information for beneficiaries in Medicare Advantage or Medicaid. Medication data was identified using Current Procedural Terminology (CPT) codes specific for aflibercept (CPT code J0178), ranibizumab (CPT code J2778), and bevacizumab (CPT codes J9035/J3490/J3590), and did not include other agents. Using a previously described method of conversion,⁴⁰ medication units were converted to number of injections using the following ratios: for bevacizumab, 1 unit:1 injection; for ranibizumab, 4 units:1 injection; for aflibercept, 2 units:1 injection. Ophthalmologists were distinguished by their National Provider Identifier numbers.

For subgroup analysis, ophthalmologists were grouped according to high-volume injection usage in 2021, defined as those within the top 10% by injection volume for each medication and those injecting high volumes of anti-VEGF agents overall (without distinguishing between medications). This produced 4 high-volume injector groups of ophthalmologists, 1 for each anti-VEGF agent and for the overall (all medications) group.

Changes in treatment protocol between 2018 and 2021 were evaluated to assess the possible effects of step therapy. This time period was chosen in order to compare the year right before step therapy implementation with the most downstream year after step therapy implementation that was available in the dataset, in order to maximize our ability to identify the effects of step therapy implementation. For the purposes of time-based comparisons, statistical analysis was limited to ophthalmologists who administered at least one injection of bevacizumab, ranibizumab, and aflibercept. Paired t-tests were utilized to assess changes in injection volumes by ophthalmologists over time. Statistical analyses were conducted using R (version 4.1.1.; R Foundation for Statistical Computing).

Results

Descriptive Statistics

From 2013 through 2021, there were 26 602 816 total injections given to Medicare Part B beneficiaries, which were attributed to 4691 ophthalmologists (Figure 1A and 1B). The average Medicare standardized payment amount was stable throughout this period (Supplemental Figure 1).

Figure 1.

(A) Injection volume (expressed as total number of injections) by antivascular endothelial growth factor (anti-VEGF) medication given to US Medicare Part B beneficiaries from 2013 to 2021. (B) Injection proportion by anti-VEGF medication from 2013 to 2021.

On a year-to-year basis, the number of new injectors (ophthalmologists performing injections in a given year but who were not present in the database for the prior year) and number of injectors who stopped injecting (ophthalmologists absent from the database for a given year after being present in the prior year) were relatively stable throughout the study period (Supplemental Figure 2). For every year of the study period other than 2021, there were a greater number of new injectors than injectors who stopped injecting. In 2021 there were 1 768 598 aflibercept injections (52.7% of total injections), 794 018 bevacizumab injections (23.7% of total injections), and 791 427 ranibizumab injections (23.6% of total injections). Notably, in 2021, fewer ophthalmologists (n = 1440) administered ranibizumab injections compared to those who administered aflibercept injections (n = 3018) and those who administered bevacizumab injections (n = 2369).

High-Volume Injector Analysis

The top 10% of injectors (high-volume injectors) overall in 2021 accounted for a total of 1 157 106 injections (34.5% of total nationwide injections), with the proportions of nationwide injections of each medication varying between each high-volume injection group (Table 1). Notably, in 2021, in the high-volume aflibercept injector group, the percentage of aflibercept injections performed in 2021 (34.5% of total nationwide aflibercept injections) was lower compared to the percentage of ranibizumab injections performed by high-volume ranibizumab injectors (43.2% of total nationwide ranibizumab injections) and compared to the percentage of bevacizumab injections performed by high-volume bevacizumab injectors (41.2% of total nationwide bevacizumab injections). These trends were consistent throughout the study period.

Table 1.

Anti–Vascular Endothelial Growth Factor Injections Given by Ophthalmologists to US Medicare Part B Beneficiaries in 2021, by All Injectors Medications/All Injectors Group and by Each High-Volume Injectors Injector Group.^a

	Total Number (%) of Injections		Mean Number of Injections
Group	All	High-Volume Injectors^b	All	High-Volume Injectors^c
All Medications	3 354 044 (100)	1 157 106 (34.5)	491	3306
Aflibercept	1 768 598 (52.7)	571 096 (32.3)	586	1897
Ranibizumab	791 427 (23.6)	341 827 (43.2)	549	2374
Bevacizumab	794 018 (23.7)	326 967 (41.2)	335	1385

High volume is defined as the top 10% of injectors for each group.

Percentages calculated as a proportion of the total number of injections for each group.

Mean values represent the average number of injections performed by the top 10% of injectors for each group.

When assessing which ophthalmologists were in each high-volume injector group defined by medication, there were variable amounts of ophthalmologist overlap between any of these 3 groups and the medication-nonspecific (all medications) high-volume injector group (ie, overlap defined as the proportion of ophthalmologists in a high-volume injection group categorized by medication who were also in the all medication high-volume injection group). The high-volume ranibizumab group had the highest degree of overlap with the overall high-volume injection group (95.8% overlap, compared with 87.0% overlap between the high-volume aflibercept group and overall group, and 80.9% overlap between the high-volume bevacizumab group and overall group). In contrast, there were much lower levels of ophthalmologist overlap across each of the high-volume injector groups defined by each medication. In particular, 22.9% of high-volume ranibizumab injectors and 18.2% of high-volume bevacizumab injectors were also present in the high-volume aflibercept group, while only 4.2% of high-volume ranibizumab injectors were also present in the high-volume bevacizumab group. Similar associations were observed when the relative frequency of each medication’s use was assessed for differences across the high-volume injector groups (Figure 2).

Figure 2.

Frequency of medication use in 2018 and 2021 across different high-volume injector groups of ophthalmologists (defined as the top 10% of injectors) administering intravitreal antivascular endothelial growth factor injections to US Medicare Part B beneficiaries: (A) aflibercept, (B) bevacizumab, and (C) ranibizumab.

Step Therapy Analysis

Changes to treatment protocol between 2018 and 2021 were evaluated to assess the possible effects of step therapy. From 2018 through 2021, there were 13 085 904 injections attributed to 4084 ophthalmologists (Table 2). Total injection volume was stable during this time. The relative usage of aflibercept increased by 32.0%, while bevacizumab’s relative usage decreased by 33.2% and ranibizumab’s relative usage decreased slightly by 4.3%. During this study period, all high-volume injector subgroups of ophthalmologists increased their aflibercept injection volume (all P < .0001 from 2018 to 2021), and both the high-volume aflibercept and high-volume ranibizumab injector groups, but not the high-volume bevacizumab injector group, decreased their bevacizumab injection volume (P < .05 for both groups from 2018 to 2021) (Table 3).

Table 2.

Presumed Impact of Step Therapy on AntiVascular Endothelial Growth Factor Injections Given to US Medicare Part B Beneficiaries From 2018 to 2021.

	Total Number of Injections (% of All Injections)
Group	2018	2019	2020	2021	Total
Aflibercept	1 268 343 (39.9)	1 458 147 (43)	1 534 168 (48.4)	1 768 598 (52.7)	6 029 256 (46.1)
Bevacizumab	1 124 732 (35.4)	1 071 897 (31.6)	840 347 (26.5)	794 018 (23.7)	3 830 994 (29.3)
Ranibizumab	782 978 (24.7)	857 155 (25.3)	794 094 (25.1)	791 427 (23.6)	3 225 654 (24.6)
Total	3 176 053	3 387 199	3 168 609	3 354 043	13 085 904

Table 3.

Presumed Impact of Step Therapy on AntiVascular Endothelial Growth Factor Injection Volume Among US Medicare Part B Beneficiaries Across Different High-Volume Subgroups From 2018 to 2021.

	Change in Injection Volume, 2018 to 2021 (P Value)
Group	Total Injections	Aflibercept Injections	Ranibizumab Injections	Bevacizumab Injections
All medications	Increase (< .0001)^a	Increase (< .0001)^a	Increase (.0018)^a	Decrease (.0037)^a
Aflibercept	Increase (< .0001)^a	Increase (< .0001)^a	No change (.38)	Decrease (< .0001)^a
Ranibizumab	Increase (.0017)^a	Increase (< .0001)^a	No change (.094)	Decrease (.012)^a
Bevacizumab	Increase (.00019)^a	Increase (< .0001)^a	Increase (.039)^a	No change (.86)

Significant change (P < .05).

Conclusions

During our study period of 2013 through 2021, there were more than 26 million anti-VEGF injections given by 4691 ophthalmologists. We identified a number of important trends in anti-VEGF injection usage, both by assessing usage over the period of 2013–2021 and by comparing data immediately before and after the implementation of step therapy. While other studies have examined anti-VEGF usage with earlier versions of Medicare Part B claims data (through 2015), to our knowledge this is the first study to utilize this data source to examine trends across a wider time range as well as before and after the implementation of step therapy (which first began in 2019) and during the COVID-19 pandemic.⁴⁰

The findings showed that a relatively small proportion (10%) of ophthalmologists accounted for a high proportion (34.5%) of the nationwide anti-VEGF injections, with a lower proportion of aflibercept injections being performed by high-volume aflibercept injectors (32.3% of nationwide aflibercept injections) when compared with the proportion of ranibizumab injections performed by high-volume ranibizumab injectors (43.2%) or proportion of bevacizumab injections performed by high-volume bevacizumab injectors (41.2%). These proportions and differences were consistent throughout the entire study period of 2013 through 2021. These findings, combined with the shift in aflibercept usage, which gradually increased from having a modest share of the total nationwide injections (20.4% of all anti-VEGF injections in 2013) to becoming a majority of the nationwide injections (52.7% of all anti-VEGF injections in 2021), support the idea that aflibercept has progressively become the most widely used of the 3 agents in our patient cohort of Medicare Part B beneficiaries. Additionally, the relatively stable proportion of aflibercept injections attributed to high-volume injectors suggests that nationwide increases in aflibercept usage could be attributed to volume changes among a broad set of ophthalmologists, rather than being solely driven by a high-volume injector subset of ophthalmologists.

Another interesting comparison that highlights aflibercept’s widespread use is the degree of enrichment (increase over and above the average injection volume) in injection volume between all ophthalmologists and the high-volume injector subgroups. The largest enrichment was seen with the high-volume ranibizumab injector group, which exhibited a 4.3-fold increase in the average number of annual ranibizumab injections compared to all ophthalmologists in 2021 (mean number of ranibizumab injections, 2374 vs 549). The high-volume bevacizumab injector group showed a similar enrichment in bevacizumab injection volume compared to all ophthalmologists in 2021 (4.1-fold increase; mean number of injections, 1385 vs 324), whereas high-volume aflibercept injectors showed a much more modest enrichment in aflibercept volume compared to all ophthalmologists in 2021 (3.2-fold increase; mean number of injections, 1897 vs 586). This further underscores the observation that, from 2013 to 2021, aflibercept evolved to become the most broadly used anti-VEGF agent across all ophthalmologists, with high-volume injectors playing less of a role in overall injection volume than for ranibizumab and bevacizumab.

Another interesting finding of this study was that fewer ophthalmologists overall chose ranibizumab for treatment in this cohort. In 2021, only 1440 ophthalmologists utilized ranibizumab injections, compared to 3018 ophthalmologists who utilized aflibercept injections and 2369 ophthalmologists who utilized bevacizumab injections. When the change in the number of ophthalmologists injecting each medication from 2013 to 2021 was assessed, aflibercept exhibited a 64% increase while bevacizumab showed a 16.9% decrease and ranibizumab demonstrated an 11.5% decrease. This change in the number of ophthalmologists injecting each medication mirrors the overall trends in medication usage. An additional observation was that each ophthalmologist tended to opt for primarily aflibercept and bevacizumab injections or aflibercept and ranibizumab injections, but it was much less common for an ophthalmologist to choose primarily ranibizumab and bevacizumab injections. These observations are consistent with previous studies examining Medicare Part B claims data from 2012 through 2015.⁴⁰

When comparing the period before step therapy versus after step therapy (2018 vs 2021), a few notable trends emerged. Contrary to what would be expected for step therapy’s intended effects, there was a significant increase in aflibercept injections and a decline in bevacizumab injections. The trend of increased aflibercept injections was mirrored by all the high-volume injector subgroups, and the decline in bevacizumab injections was reflected by 2 of the 3 high-volume injector subgroups, other than the high-volume bevacizumab group. While it is possible there may be a more narrowly defined subset of high-volume injectors who defy these trends, these findings reassert the possibility that there may not be fundamental differences in the trends that occur across all ophthalmologists versus only within high-volume subgroups.

There are a few notable limitations to this study. Our dataset comprised solely injection data for Medicare Part B beneficiaries, and as such does not offer insights into trends for patients with private insurance, Medicare Advantage, or Medicaid. Notably, Medicare Part B beneficiaries are not subject to fail-first therapy. It is also possible that some injections may be omitted from the CMS dataset entirely, but we have no reason to believe this is a significant characteristic of this dataset. An additional inherent limitation of the CMS dataset is that it does not differentiate retina specialists from all ophthalmologists. However, the high-volume injector groups are likely nearly entirely composed of retina specialists. Short of closely examining the training credentials of all 4691 ophthalmologists identified in this study, there is no reliable way to perfectly distinguish between retina specialists and non–retina specialists.

An additional limitation is that our study was only able to analyze the effects of step therapy on anti-VEGF usage changes for 2 full years of data following the initial implementation of step therapy. Given that medication choice is most relevant for patients being newly initiated on anti-VEGF injections, and a relatively small proportion of ophthalmologists’ patient panels fall into this category in any singular year (as opposed to the many patients who are continuing a preexisting anti-VEGF regimen), it is possible the full effects of step therapy may not yet be reflected in the available CMS data.

It is also possible that some clinicians use bevacizumab for initial treatment while awaiting insurance coverage for other drugs, and the Medicare database does not provide sufficient granularity to explore this possibility. An additional inherent limitation of the Medicare Part B claims dataset is that it fails to offer insight into the decisions made by individual physicians when deciding which medication to use for a given patient. Another important consideration is that there have been previously documented supply-chain issues with bevacizumab, and our data is unable to account for the possibility that these issues may be partially responsible for the decline in bevacizumab injections in 2020.⁴¹ An additional contextual factor for this study is that the later time range of our dataset coincides with the height of the COVID-19 pandemic. While it is not immediately obvious how the COVID-19 pandemic may have impacted the usage patterns we identified, we cannot exclude the possibility that the pandemic may have had unforeseen effects on our dataset.

Despite these limitations, our dataset is the most optimal source of currently available information for assessing nationwide trends. Another interesting facet of anti-VEGF usage trends impacted by step therapy is the role of biosimilars and other newly approved drugs. The current landscape is certainly very different than that of the time range evaluated in this study, and therefore, this study may not be generalizable to current trends. Although the time range of our dataset does not provide the opportunity to evaluate the use of biosimilars (for example, ranibizumab-nuna [Byooviz; Samsung Bioepis Co., Ltd.] was the first ranibizumab biosimilar given FDA approval for neovascular AMD, in 2021), it would certainly be an interesting future direction to compare usage trends of aflibercept, ranibizumab, and bevacizumab with those of anti-VEGF biosimilars, for which the Medicare Part B dataset would be well-suited.⁴² An additional future direction that could prove interesting would be to analyze the impact of fail-first requirements enacted by private insurers, though this would require a different source of data that may not be as readily available as the Medicare Part B database, and such an investigation would likely entail different considerations during data analysis.

Supplemental Material

sj-png-1-vrd-10.1177_24741264251383410 – Supplemental material for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era

Supplemental material, sj-png-1-vrd-10.1177_24741264251383410 for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era by John M. Bryan, Neil Sheth and Michael J. Heiferman in Journal of VitreoRetinal Diseases

Supplemental Material

sj-png-2-vrd-10.1177_24741264251383410 – Supplemental material for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era

Supplemental material, sj-png-2-vrd-10.1177_24741264251383410 for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era by John M. Bryan, Neil Sheth and Michael J. Heiferman in Journal of VitreoRetinal Diseases

Footnotes

Ethical Approval

Approval was not needed because of the study type (no human participants).

Statement of Informed Consent

This study did not involve human subjects and the data for this study was from a publicly available database without personally identifiable information. Consequently, informed consent is not applicable.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by an unrestricted departmental grant from Research to Prevent Blindness.

ORCID iDs

John M. Bryan

Neil Sheth

Michael J. Heiferman

Data Availability

The data used for this study is from a publicly available database on the CMS website. The authors are also able to provide the data used for this study upon request.

Supplemental Material

Supplemental material is available online with this article.

References

Leung

Cachianes

Kuang

Goeddel

Ferrara

Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306-1309. doi:10.1126/science.2479986

Keck

Hauser

Krivi

, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309-1312. doi:10.1126/science.2479987

Adamis

AP.

Inhibition of vascular endothelial growth factor prevents retinal ischemia—associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114(1):66. doi:10.1001/archopht.1996.01100130062010

Robinson

Pierce

Rook

Foley

Webb

Smith

LE.

Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci U S A. 1996;93(10):4851-4856. doi:10.1073/pnas.93.10.4851

Ozaki

Seo

Ozaki

, et al. Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol. 2000;156(2):697-707. doi:10.1016/S0002-9440(10)64773-6

Sternberg

Durrani

AK.

Evolving concepts in the management of retinopathy of prematurity. Am J Ophthalmol. 2018;186:xxiii-xxxii. doi:10.1016/j.ajo.2017.10.027

Kim

D’Amore

PA.

A brief history of anti-VEGF for the treatment of ocular angiogenesis. Am J Pathol. 2012;181(2):376-379. doi:10.1016/j.ajpath.2012.06.006

Aiello

Pierce

Foley

, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995;92(23):10457-10461. doi:10.1073/pnas.92.23.10457

Gordon

Margolin

Talpaz

, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843-850. doi:10.1200/JCO.2001.19.3.843

10.

Kabbinavar

Hurwitz

Fehrenbacher

, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60-65. doi:10.1200/JCO.2003.10.066

11.

Hurwitz

Fehrenbacher

Novotny

, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342. doi:10.1056/NEJMoa032691

12.

Michels

Rosenfeld

Puliafito

Marcus

Venkatraman

Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6):1035-1047.e9. doi:10.1016/j.ophtha.2005.02.007

13.

Rosenfeld

Moshfeghi

Puliafito

CA.

Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin^®) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335. doi:10.3928/1542-8877-20050701-14

14.

Chen

Wiesmann

Fuh

, et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured fab in complex with antigen. J Mol Biol. 1999;293(4):865-881. doi:10.1006/jmbi.1999.3192

15.

Rosenfeld

Brown

Heier

, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. doi:10.1056/NEJMoa054481

16.

Brown

Kaiser

Michels

, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. doi:10.1056/NEJMoa062655

17.

Campochiaro

Heier

Feiner

, et al. Ranibizumab for macular edema following branch retinal vein occlusion. Ophthalmology. 2010;117(6):1102-1112.e1. doi:10.1016/j.ophtha.2010.02.021

18.

Brown

Campochiaro

Bhisitkul

, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118(8):1594-1602. doi:10.1016/j.ophtha.2011.02.022

19.

Brown

Campochiaro

Singh

, et al. Ranibizumab for macular edema following central retinal vein occlusion. Ophthalmology. 2010;117(6):1124-1133.e1. doi:10.1016/j.ophtha.2010.02.022

20.

Campochiaro

Brown

Awh

, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041-2049. doi:10.1016/j.ophtha.2011.02.038

21.

Nguyen

Brown

Marcus

, et al. Ranibizumab for diabetic macular edema. Ophthalmology. 2012;119(4):789-801. doi:10.1016/j.ophtha.2011.12.039

22.

Massin

Bandello

Garweg

, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study). Diabetes Care. 2010;33(11):2399-2405. doi:10.2337/dc10-0493

23.

Holash

Davis

Papadopoulos

, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393-11398. doi:10.1073/pnas.172398299

24.

Heier

Brown

Chong

, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006

25.

Campochiaro

Clark

Boyer

, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion. Ophthalmology. 2015;122(3):538-544. doi:10.1016/j.ophtha.2014.08.031

26.

Korobelnik

Schmidt-Erfurth

, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254. doi:10.1016/j.ophtha.2014.05.006

27.

CATT Research Group; Martin

Maguire

, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908. doi:10.1056/NEJMoa1102673

28.

Solomon

Lindsley

Vedula

Krzystolik

Hawkins

BS.

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;8(8):CD005139. doi:10.1002/14651858.CD005139.pub3

29.

Sarwar

Clearfield

Soliman

, et al. Aflibercept for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2016;2(2):CD011346. doi:10.1002/14651858.CD011346.pub2

30.

Diabetic Retinopathy Clinical Research Network; Wells

Glassman

, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264

31.

Wells

Glassman

Ayala

, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359. doi:10.1016/j.ophtha.2016.02.022

32.

Scott

VanVeldhuisen

, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial. JAMA. 2017;317(20):2072. doi:10.1001/jama.2017.4568

33.

Narayanan

Panchal

Das

Chhablani

Jalali

Ali

. A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J Ophthalmol. 2015;99(7):954-959. doi:10.1136/bjophthalmol-2014-306543

34.

Hykin

Prevost

Vasconcelos

, et al. Clinical effectiveness of intravitreal therapy with ranibizumab vs aflibercept vs bevacizumab for macular edema secondary to central retinal vein occlusion: a randomized clinical trial. JAMA Ophthalmol. 2019;137(11):1256-1264. doi:10.1001/jamaophthalmol.2019.3305

35.

Jhaveri

Glassman

Ferris

, et al. Aflibercept monotherapy or bevacizumab first for diabetic macular edema. N Engl J Med. 2022;387(8):692-703. doi:10.1056/NEJMoa2204225

36.

Ross

Hutton

Stein

, et al. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the Diabetic Retinopathy Clinical Research Network comparative effectiveness trial. JAMA Ophthalmol. 2016;134(8):888-896. doi:10.1001/jamaophthalmol.2016.1669

37.

Mott

. Step therapy: clinicians’ concerns and challenges. EyeNet Magazine. April 2022:26-28.

38.

Gallemore

Nguyen

When anti-VEGF treatment fails. March 2008. Accessed May 26, 2023. https://www.reviewofophthalmology.com/article/when-anti-vegf-treatment-fails#:~:text=Some%20clinicians%20identify%20a%20treatment,despite%20a%20course%20of%20treatment

39.

Centers for Medicare & Medicaid Services. Medicare physician & other practitioners - by provider and service. May 2023. Accessed August 13, 2023. https://data.cms.gov/provider-summary-by-type-of-service/medicare-physician-other-practitioners/medicare-physician-other-practitioners-by-provider-and-service

40.

Berkowitz

Sternberg

Feng

Chen

Patel

Analysis of anti–vascular endothelial growth factor injection claims data in US Medicare Part B beneficiaries from 2012 to 2015. JAMA Ophthalmol. 2019;137(8):921. doi:10.1001/jamaophthalmol.2019.1971

41.

American Academy of Ophthalmology. Avastin shortages: academy, retina specialists ramp up efforts to address the issue. June 2021. Accessed March 31, 2023. https://www.aao.org/eye-on-advocacy-article/avastin-shortages-academy-retina-specialists-ramp

42.

U.S. Food and Drug Administration. FDA approves first biosimilar to treat macular degeneration disease and other eye conditions. September 2021. Accessed May 26, 2023. https://web.archive.org/web/20230510231638/https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treat-macular-degeneration-disease-and-other-eye-conditions

Supplementary Material

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Trends in AntiVascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era

Abstract

Keywords

Introduction

Methods

Results

Descriptive Statistics

High-Volume Injector Analysis

Step Therapy Analysis

Conclusions

Supplemental Material

sj-png-1-vrd-10.1177_24741264251383410 – Supplemental material for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era

Supplemental Material

sj-png-2-vrd-10.1177_24741264251383410 – Supplemental material for Trends in Anti–Vascular Endothelial Growth Factor Injections Among Medicare Part B Beneficiaries in 2013–2021 and the Step Therapy Era

Footnotes

Ethical Approval

Statement of Informed Consent

Declaration of Conflicting Interests

Funding

ORCID iDs

Data Availability

Supplemental Material

References

Supplementary Material