Abstract
Objective
To determine the effectiveness of bevacizumab step therapy for neovascular age-related macular degeneration (nAMD) in routine clinical practice.
Methods
In this retrospective case series, eyes initiating treatment for nAMD at an academic medical centre from 2011–2019 were included. Exclusion criteria included previous intravitreal anti-VEGF injections, prior non-cataract intraocular surgery, <1 year of treatment, and not starting on monthly bevacizumab therapy. Of 895 eligible eyes, 548 were excluded, yielding 347 eyes in the study population.
These eyes were treated for nAMD under the bevacizumab step therapy protocol with an option to switch to another agent in the event of predefined treatment failure. Treatment failure was defined as losing 15 or more Early Treatment Diabetic Retinopathy Study letters or switching to an alternative anti-VEGF agent. Eyes that did not meet these criteria were deemed treatment successes. Annual change in mean VA from baseline (ΔVA) was the primary outcome. Secondary outcomes included treatment success rate, medication switch rate, and post-switch ΔVA.
Results
After 1 year, mean ΔVA was +8.4 letters (95% CI: +6.1 to +10.6 letters). 86% had treatment success, and 6% of eyes had switched to aflibercept. In years 2–7, ΔVA ranged from +7.0 to −0.7 letters, and treatment success rates ranged from 68 to 82%. 11% (n = 38) of eyes were switched to aflibercept. The post-switch ΔVA in these eyes was −7.1 letters (95% CI: −13.3 to −0.1) after a mean of 17.7 ± 12.6 injections over an average of 2.7 ± 2.0 years.
Conclusion
A bevacizumab step therapy protocol in routine clinical practice is effective for long-term treatment of nAMD.
Subject terms: Outcomes research, Retinal diseases
Introduction
Since the Ocular Neovascularization Clinical Trial Group first reported the efficacy of intravitreal pegaptanib in 2004, anti-vascular endothelial growth factor (anti-VEGF) therapy has become the standard of care for managing neovascular age-related macular degeneration (nAMD) [1]. Currently, four anti-VEGF agents are commercially available and used in the United States for treating nAMD—aflibercept (Eylea, Regeneron, Tarrytown, NY), ranibizumab (Lucentis, Genentech, San Francisco, CA), brolucizumab (Beovu, Novartis, Basel, Switzerland), and bevacizumab (Avastin, Genentech, San Francisco, CA). While aflibercept, ranibizumab, and brolucizumab are FDA-approved for nAMD, bevacizumab use in ophthalmology is off-label. Despite its lack of FDA-approval, bevacizumab is the most commonly used anti-VEGF agent for the treatment of nAMD in the United States [2].
In a landmark 2011 randomized control trial, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group found that bevacizumab and ranibizumab had equivalent visual outcomes after 1 and 2 years of treatment [3, 4].
Multiple subsequent prospective level 1 randomized clinical trials performed outside the US have all concluded that bevacizumab is noninferior to ranibizumab in regards to visual acuity (VA) and adverse effect profile in the treatment of nAMD [5–8]. Furthermore, subsequent meta-analyses, clinical trials, and retrospective analyses have reported similar visual outcomes among the available anti-VEGF agents [9–14]. However, the four drugs differ dramatically in cost. The FDA-approved agents ranibizumab, aflibercept, and brolucizumab cost approximately $1950, $1850, and $1850 per dose in the US, respectively [15, 16]. In contrast, off-label bevacizumab costs approximately $60 per injection, and its use resulted in an estimated Medicare and patient savings of $17.3 billion from 2008 to 2015 for the treatment of nAMD [17, 18]. Recent data demonstrate that despite the cost savings associated with bevacizumab usage, over one-third of physicians continue using more expensive agents as first-line therapy [19, 20].
Given the high costs of FDA-approved anti-VEGF agents and level 1 data supporting the comparative efficacy of bevacizumab for the treatment of nAMD, there is increasing advocacy for bevacizumab step therapy. In such a protocol, all patients with nAMD are started on bevacizumab. Patients who achieve treatment success are maintained on bevacizumab while those who fail bevacizumab can be switched to an alternative medication.
In 2019, the Centers for Medicare and Medicaid Services (CMS) allowed Medicare Advantage plans the option to implement step therapy for physician-administered and other Part B drugs in an effort to cut costs [21]. The American Academy of Ophthalmology (AAO) called the move “inappropriate,” noting evidence that ranibizumab and aflibercept have better outcomes than bevacizumab for diabetic macular oedema [22]. The AAO also argued step therapy is already required by some private commercial payers with questionable patient outcomes, emphasizing that the most appropriate course of treatment depends on the patient’s unique disease course and clinical situation [22].
There is ample evidence demonstrating the equal efficacy of bevacizumab compared to the FDA-approved agents in the setting of nAMD [3–10, 14]. However, to date, no long-term research exists on the effectiveness of a step therapy protocol starting with bevacizumab for nAMD. In 2012, in response to the release of the CATT data, the Vanderbilt Eye Institute (VEI) retina division developed a consensus treatment algorithm for nAMD. The result was a step therapy protocol, whereby all patients received bevacizumab as their initial treatment. The purpose of this study is to evaluate the long-term outcomes of patients treated under this protocol in order to provide information on the effectiveness of bevacizumab step therapy for nAMD.
Methods
Approval for this retrospective observational case series was obtained from the Institutional Review Board (Vanderbilt University, #191136). Informed consent was not required for this retrospective case series. Data was collected from the electronic medical record and was compliant with the Health Insurance Portability and Accountability Act. The study adhered to the tenets of the Declaration of Helsinki.
Step therapy protocol
In the VEI nAMD step therapy protocol, all patients began treatment with four injections of bevacizumab at 4-week intervals. If the disease was controlled, providers then had the option of increasing subsequent injection intervals up to 8 weeks (q8) in two week intervals. If, at any subsequent point, the provider determined that neovascular disease was not controlled, the interval between bevacizumab injections could be decreased down to a minimum of every 4 weeks, or the patient could be switched to an alternative agent.
Data collection
Medical record numbers of patients who received anti-VEGF injections at VEI between January 1, 2012 and December 31, 2019 were collected from the electronic medical record using the intravitreal injection Common Procedural Terminology (CPT) code 67028. In patients who were treated bilaterally, each eye was analysed individually. Eyes were excluded if they had previous intravitreal anti-VEGF injections prior to the study window, had an injection indication other than nAMD, were not started on monthly bevacizumab for at least the first 4 injections, had less than 8 months of treatment, or had past intraocular surgery other than uncomplicated cataract removal.
Procedure notes of intravitreal injections were reviewed to determine visual acuities, presence of a drug switch, and the interval between injections. Eyes were judged to have graduated to an 8-week interval if at least the last three consecutive injection intervals were separated by 8 weeks without clinician-determined necessity to shorten the interval. These data were recorded up to 7 years of follow-up at injection visits through December 31, 2020. In addition, the duration of treatment and total number of injections were recorded along with patient age, sex, smoking history, and diabetes status. Finally, procedure notes of eyes that switched intravitreal agents were reviewed to determine VA change before and after switching.
Analysis
The annual change in mean VA from baseline (ΔVA) was the primary outcome. Secondary outcomes included the annual bevacizumab treatment success rate, medication switch rate, and graduation rate to an 8-week injection interval as well as the visual acuity change after switching agents.
In previous anti-VEGF AMD studies, including the ANCHOR, MARINA, and VIEW1/2 trials, treatment failure has been defined as loss of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters [9, 23, 24]. In this study, we supplemented that definition by also including all eyes that were switched to an alternative agent due to neovascular disease recurrence as failures, regardless of their final vision change. Eyes that did not meet these criteria were deemed treatment successes.
Outcomes were analysed annually at years 1–7. Eyes were only included in each year’s analysis if they had an injection within 3 months of the anniversary of the first injection. Snellen visual acuities were converted to ETDRS letter scores using a published algorithm [25]. Descriptive statistics were employed for this analysis using Microsoft Excel (Redmond, Washington).
Results
Study population
The eligible population included 895 eyes (745 patients) that initiated intravitreal injections for nAMD at VEI between January 1, 2012 and December 31, 2019. 548 eyes met the exclusion criteria, and the final study population consisted of 347 eyes (306 patients). The mean baseline VA of the study population was 44.3 letters. The demographic characteristics and of the study population are summarized in Table 1.
Table 1.
Baseline characteristics of patients.
| All Eyes (n = 347) | |
|---|---|
| Age in years (mean ± SD) | 79.8 ± 8.4 |
| Breakdown of age in years | |
| ≤64 | 11 (3.2) |
| 65–74 | 70 (20.2) |
| 75–84 | 159 (45.8) |
| 85–94 | 104 (30.0) |
| ≥95 | 3 (0.9) |
| Sex | |
| Female | 224 (64.6) |
| Male | 123 (35.4) |
| History of diabetes | |
| Yes | 96 (27.7) |
| No | 251 (72.3) |
| History of smoking | |
| Yes | 101 (29.1) |
| No | 246 (70.9) |
| Baseline VA letter score (mean ± SD) | 44.3 ± 25.3 |
Data are “number of patients (%)” unless otherwise indicated.
Annual visual acuity change from baseline
Mean ΔVA from baseline was +8.4 letters (95% CI: +6.1 to +10.6 letters) at 1 year and remained above baseline for the first 6 years of treatment (Table 2). It decreased to +7.0 letters (95% CI: +4.4 to +9.7 letters) and +4.0 letters (95% CI: +0.5 to +7.5 letters) in the second and third years, respectively. Vision remained stable at +4.3 (95% CI: +0.4 to +8.1 letters), +4.4 (95% CI: −0.4 to +9.3 letters), and +4.2 (95% CI: −2.0 to +10.5 letters), in years 4–6 before dropping to −0.7 (95% CI: −8.0 to +6.7 letters) in year 7.
Table 2.
Annual visual acuity and treatment course outcomes.
| 1 Year | 2 Years | 3 Years | 4 Years | 5 Years | 6 Years | 7 Years | |
|---|---|---|---|---|---|---|---|
| Number of eyes | 347 | 261 | 192 | 153 | 109 | 75 | 37 |
| Years of treatment (mean ± SD) | 1.00 ± 0.07 | 2.02 ± 0.08 | 3.02 ± 0.09 | 4.01 ± 0.08 | 5.00 ± 0.08 | 6.00 ± 0.09 | 7.01 ± 0.09 |
| Total injections (mean ± SD) | 9.3 ± 1.6 | 16.0 ± 3.8 | 22.4 ± 4.8 | 29.0 ± 6.4 | 35.4 ± 8.0 | 41.5 ± 12.4 | 47.9 ± 9.8 |
| Baseline VA letter score (mean ± SD) | 44.3 ± 25.3 | 44.8 ± 25.1 | 45.6 ± 25.5 | 45.9 ± 25.4 | 46.1 ± 24.5 | 46.1 ± 25.0 | 46.3 ± 26.6 |
| Final VA letter score (mean ± SD) | 52.7 ± 25.2 | 51.9 ± 25.9 | 49.5 ± 27.2 | 50.2 ± 26.0 | 50.5 ± 24.2 | 50.3 ± 24.6 | 45.6 ± 24.2 |
| VA letter score change from baseline | |||||||
| Mean±SD | 8.4 ± 21.5 | 7.0 ± 22.1 | 4.0 ± 24.8 | 4.3 ± 24.2 | 4.4 ± 26.0 | 4.2 ± 27.6 | −0.7 ± 22.8 |
| 95% Confidence Interval | 6.1 to 10.6 | 4.4 to 9.7 | 0.5 to 7.5 | 0.4 to 8.1 | −0.4 to 9.3 | −2.0 to 10.5 | −8.0 to 6.7 |
| Breakdown of VA letter score change | |||||||
| ≥15 decrease | 31 (8.9) | 29 (11.1) | 33 (17.2) | 21 (13.7) | 18 (16.5) | 17 (23) | 6 (16) |
| 5–14 decrease | 28 (8.1) | 21 (8.0) | 15 (7.8) | 18 (11.8) | 8 (7.3) | 8 (11) | 5 (14) |
| <5 change | 111 (32.0) | 76 (29.1) | 53 (27.6) | 43 (28.1) | 35 (32.1) | 15 (20) | 11 (30) |
| 5–14 increase | 66 (19.0) | 56 (21.5) | 36 (18.8) | 24 (15.7) | 15 (13.8) | 9 (12) | 8 (22) |
| ≥15 increase | 111 (32.0) | 79 (30.3) | 55 (28.6) | 47 (30.7) | 33 (30.3) | 26 (35) | 7 (19) |
| Treatment Course | |||||||
| Success | 297 (85.6) | 214 (82.0) | 145 (75.5) | 119 (77.8) | 81 (74.3) | 51 (68) | 28 (76) |
| Failure | 50 (14.4) | 47 (18.0) | 47 (24.5) | 34 (22.2) | 28 (25.7) | 24 (32) | 9 (24) |
| Breakdown of Success/Failure cohorts | |||||||
| Success, maintained on q8 week bevacizumab | 189 (54.5) | 157 (60.2) | 112 (58.3) | 95 (62.1) | 64 (58.7) | 44 (59) | 23 (62) |
| Success, maintained on < q8 week bevacizumab | 108 (31.1) | 57 (21.8) | 33 (17.2) | 24 (15.7) | 17 (15.6) | 7 (9) | 5 (14) |
| Failure, switch to aflibercept | 22 (6.3) | 22 (8.4) | 21 (10.9) | 17 (11.1) | 13 (11.9) | 10 (13) | 6 (16) |
| Failure, not switched at provider discretion | 28 (8.1) | 25 (9.6) | 26 (13.5) | 17 (11.1) | 15 (13.8) | 14 (19) | 3 (8) |
Data are “number (%)” unless otherwise indicated.
Table 2 shows the breakdowns of baseline VA, final VA, and ΔVA by year. 8.9% of eyes lost 15+ letters at 1 year while 32.0% gained 15+ letters. 30.1% of eyes undergoing 5 years of treatment maintained a 15+ letter gain from baseline.
Step therapy treatment course
At 1 year, 85.6% of eyes had treatment success and were maintained on a stable bevacizumab regimen at 12 months (Fig. 1). 54.5% achieved treatment success with an 8-week bevacizumab injection interval. 31.1% achieved treatment success with a bevacizumab injection interval <8 weeks. 14.4% of eyes failed bevacizumab treatment at 12 months. 6.3% of eyes failed bevacizumab and were switched to aflibercept, and 8.1% of eyes failed bevacizumab but were not switched to an alternative agent by the treating clinician.
Fig. 1. Secondary outcomes for 1 and 5 year analyses.
The left side of the figure shows the step therapy treatment success and failure outcomes after 1 year of treatment. The success and failure cohorts are further broken down by treatment regimen and the presence or absence of a medication switch. The right side of the figure shows these outcomes after 5 years of treatment.
Treatment success rates in years 2–7 remained high, ranging between 68 and 82%. As the follow-up time increased, the percentage of eyes that were switched to aflibercept consistently increased, up to 13 and 16% of eyes that completed 6 and 7 years of follow-up, respectively. The percentage of eyes maintained on q8 week bevacizumab stabilized between 58–62% in years 2–7 while the percentage of eyes on a bevacizumab regimen <q8 week steadily decreased with longer follow-up. Figure 1 shows the contrast in treatment course outcomes after undergoing treatment for 1 year and 5 years, respectively.
Visual acuity outcomes of eyes that switched agents are shown in Table 3. These eyes received a mean (±SD) of 12.2 ± 10.4 bevacizumab injections over 1.3 ± 1.0 years before switching, followed by 17.7 ± 12.6 injections of an alternative agent over 2.7 ± 2.0 years. The mean letter change before switching was −5.3 letters (95% CI: −10.0 to −0.7), and these eyes had an additional change of −7.1 letters (95% CI: −12.9 to −1.3 letters) after switching. From the time of the switch, 18.4% of eyes gained at least 5 letters, and 10.5% of eyes gained 15 or more letters.
Table 3.
Visual acuity outcomes of treatment switch population (n = 38).
| Baseline | Switch | Final | |
|---|---|---|---|
| VA letter score (mean ± SD) | 59.8 ± 15.3 | 54.5 ± 20.6 | 47.4 ± 26.2 |
| Breakdown of VA letter score | |||
| 0–19 (VA < 20/400) | 1 (3) | 3 (8) | 7 (18) |
| 20–34 (20/400 ≤ VA < 20/200) | 0 (0) | 2 (5) | 1 (3) |
| 35–49 (20/200 ≤ VA < 20/100) | 4 (11) | 5 (13) | 4 (11) |
| 50–64 (20/100 ≤ VA < 20/50) | 17 (45) | 15 (40) | 14 (37) |
| 65–79 (20/50 ≤ VA < 20/25) | 14 (37) | 11 (29) | 11 (29) |
| 80–95 (VA ≥ 20/25) | 2 (5) | 2 (5) | 1 (3) |
| Baseline→Switch | Switch→Final | Baseline→Final | |
| Intravitreal agent | Bevacizumab | Aflibercept | Both |
| Years of treatment (mean ± SD) | 1.28 ± 0.97 | 2.65 ± 2.03 | 3.94 ± 2.31 |
| Number of injections (mean ± SD) | 12.2 ± 10.4 | 17.7 ± 12.6 | 29.8 ± 16.8 |
| VA letter score change | |||
| Mean ± SD | −5.3 ± 14.6 | −7.1 ± 18.3 | −12.5 ± 21.2 |
| 95% Confidence Interval | −10.0 to −0.7 | −12.9 to −1.3 | −19.2 to −5.7 |
| Breakdown of VA letter score change | |||
| ≥15 decrease | 8 (21) | 9 (24) | 12 (32) |
| 5–14 decrease | 7 (18) | 5 (13) | 10 (26) |
| <5 change | 14 (37) | 17 (45) | 8 (21) |
| 5–14 increase | 6 (16) | 3 (8) | 6 (16) |
| ≥15 increase | 3 (8) | 4 (11) | 2 (5) |
Data are “number (%)” unless otherwise indicated.
Discussion
Here, we report effectiveness outcomes of a bevacizumab step therapy protocol for treatment of nAMD. Eyes that lost 15 letters or more or required switching to another anti-VEGF agent were deemed failures. Our data shows the success rate of bevacizumab step therapy at 12-months was 85.6% with an average gain of +8.4 letters (95% CI: +6.1 to +10.6 letters). Additionally, the mean ΔVA was +4.0 letters or more, and the overall success rate was at least 74% every year through 5 years of follow-up.
Our reported annual visual acuity results are comparable to published data on ranibizumab, aflibercept, and brolucizumab. After 12 months of ranibizumab treatment, the MARINA trial found a mean 7.2 letter increase with monthly injections while the HARBOR and CATT trials found a letter increase of +8.2 (SD = 13.3) and +6.8 (SE = 0.8), respectively, with as-needed ranibizumab injections [3, 24, 26]. Similarly, the VIEW1 trial found q8 week aflibercept to have a + 7.9 (SD = 15) letter increase at 12 months, and the HAWK and HARRIER trials found treat-and-extend brolucizumab to have a + 6.6 (SE = 0.71) and +6.9 (SE = 0.61) letter increase at 11 months, respectively [9, 14].
Our 2 year ΔVA of +7.0 letters is comparable to +7.2 and +7.9 letter change in the 24 month analysis of the MARINA and HARBOR trials [24, 26]. Bhandari et. al reported 3 year VA outcomes of +1.6 (95% CI: −1.1 to 4.3) for aflibercept and +2.4 (95% CI: −0.6 to 5.3) for ranibizumab, comparable to our finding of +4.0 letters [27]. The HORIZON study found ΔVA to be +2.0 letters in eyes treated with ranibizumab for 4 years, similar to our finding of +4.3 letters [28]. Reports of letter change at 5 and 6 years are limited, but our findings of +4.4 and +4.2 letters are consistent with a 5 year outcome of +0.7 letters found by the Fight Retinal Blindness Study Group and the 5.5 year outcome of −3.3 ± 22.3 letters found by CATT Research Group [29, 30]. Finally, our finding of −0.7 letters at 7 years is comparable to the 7 year outcomes of −2.7 letters reported by the Fight Retinal Blindness Study Group and −8.6 letters reported by the and the SEVEN-UP study [30, 31].
Our study provides novel insight into the VA outcomes of eyes that switch agents after failing bevacizumab step therapy. From the time of the switch to last follow-up, these eyes had a mean VA change of −7.1 letters (95% CI: −12.9 to −1.3 letters). These findings are comparable to corresponding post-switch ΔVA values reported by Bhandari et al., which were −3.6 letters (95% CI: −6.7 to −0.5 letters) in eyes that switched from ranibizumab to aflibercept and −3.0 letters (95% CI: −8.0 to 1.9 letters) in eyes that switched from aflibercept to ranibizumab [27]. There is no way of predicting how these patients would have done if they were started on a different treatment regimen or switched anti-VEGF agents earlier.
Our study also reveals interesting insights into the final treatment regimens for patients who were successfully treated with bevacizumab. In the 5 year analysis, 58.7% of patients were stable on q8 week bevacizumab injections. An additional 15.6% of patients were maintained on serial bevacizumab injections at a more frequent interval without significant vision loss. These findings indicate the majority of patients can achieve disease stability on an extended bevacizumab treatment regimen with excellent visual outcomes. Our findings expand upon the 2-year results from the TREX-AMD study, which reported a mean maximum extension of 8.5 weeks with ranibizumab [32].
Bhandari et al. found that after 3 years of treatment, 25.5% of patients started on ranibizumab had switched to aflibercept within the first 3 years of treatment [27]. Similarly, a review of over 30,000 eyes treated with anti-VEGF agents for nAMD found a long-term switch rate of 27.4% [33]. We hypothesized that the switch rate in our study would be similar. However, our switch rate in follow-up years 3–7 only ranged from 11 to 16%. Given the substantial cost savings of using bevacizumab instead of the other anti-VEGF agents, our finding that over 90% of patients stay on bevacizumab long-term is significant because it indicates that the cost savings of step therapy may be greater than expected.
The reasons behind the low switch rate were likely myriad. At 5 years follow-up, 13.8% of patients lost 15+ letters but were not switched to an alternative agent at provider discretion. One might speculate these decisions were driven by personal financial benefit, but physician compensation at VEI is completely unrelated to medication costs and reimbursements. In analysing this cohort of patients, we noticed that in many cases their neovascular disease was adequately controlled despite meeting our stringent VA definition of treatment failure. Their vision loss was typically gradual due to the natural progression of atrophic changes related to macular degeneration. Our analysis prohibits speculation on whether these patients would have benefited from switching to an alternative agent.
As with all retrospective studies, our results should be interpreted with caution and are limited by the study’s retrospective design. Reliance on Snellen visual acuity measurements for baseline vision and the limited sample size in follow-up years 6 and 7 are particular weaknesses. It should also be noted that this study was conducted without restriction on presenting visual acuity. In contrast, clinical trials typically limit participants to patients with baselines of 25–70 letters or 25–80 letters [3, 24, 26]. This discrepancy is a limitation because differences in baseline VA could lead to differences in average VA change. However, this diversity of baseline VA is also a strength because it makes our findings generalizable to routine clinical practice.
Step therapy will remain a controversial topic for the foreseeable future. On one hand, step therapy implemented nationally would save billions of dollars over the next decade [18, 20]. The government, insurers, and patients would all benefit financially, as Medicare has mandated that at least half of the savings in Medicare Advantage plans be passed on to patients [21]. Given the rising cost of healthcare in the US, these are important considerations, especially since aflibercept was by far the most expensive drug for Medicare Part B in 2018, totalling over $2.5 billion [17, 34]. Ranibizumab was not far behind at #7, costing $1.2 billion, bringing the total cost of these two medications to over $3.7 billion annually [34].
On the other hand, numerous arguments against step therapy have been presented. First, the AAO argued that it violates physician autonomy, noting that comorbidities, drug-drug interactions, or patient intolerances may exist that necessitate an alternative drug as initial therapy [22]. Although the CMS guidance states that exceptions can be applied for, the AAO argued that the patient’s health care provider is the best person to make that decision [21, 22].
Second, there are concerns about potential problems specifically regarding bevacizumab’s use as an off-label agent, which requires it to be repackaged by compounding pharmacies. There have been reports of medication contamination during the syringe preparation causing endophthalmitis [35]. However, a study of over 383 000 injections found no increased risk of endophthalmitis with repackaged bevacizumab compared to ranibizumab from the manufacturer [36]. Repackaged bevacizumab has also occasionally been found to contain silicone oil microdroplets which could cause floaters [37]. Furthermore, potential limited availability of the drug due to the necessary repackaging, issues with copays due to bevacizumab’s off-label status, and uncertainty on the effects of step therapy on the availability of anti-VEGF samples for the uninsured and underinsured patient populations are additional points worth consideration.
Finally, and perhaps most importantly, groups opposing step therapy have called it unsafe for patients because they say it can be used to force use of an inferior agent [22]. In the case of diabetic macular oedema, this is a valid argument, as aflibercept has been shown to have better outcomes than bevacizumab in patients with visual acuity worse than 20/50 [38, 39]. However, the literature on nAMD lacks any compelling evidence supporting the use of one anti-VEGF agent over the others. Further, despite potentially less intrinsic binding affinity, bevacizumab appears to have a significantly longer half-life in the vitreous than ranibizumab and aflibercept, which may give it a distinct advantage in a relatively low VEGF disease such as nAMD [40]. We suggest further investigation into bevacizumab step therapy for nAMD and the consideration of a more nuanced, disease-specific national policy on step therapy.
We conclude that a bevacizumab step therapy protocol implemented in routine clinical practice is effective for long-term treatment of nAMD. We hope these findings will inform the current health policy debate.
Summary
What was known before
Following release of the CATT data, bevacizumab was shown to have equal efficacy with regards to visual gains as ranibizumab in the setting of neovascular age-related macular degeneration.
What this study adds
A step therapy protocol for the treatment of neovascular age-related macular degeneration starting with four monthly bevacizumab injections with the subsequent option to switch to an alternative anti-VEGF agent was effective in routine clinical practice. After 1 year, mean ΔVA was +8.4 letters (95% CI, +6.1 to +10.6 letters).
Author contributions
SP confirms that he has had full access to the data in the study and final responsibility for the decision to submit for publication. Conceived and/or designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results: JS, SJK, PS, SP. Drafted or revised the manuscript: JS, SJK, PS, SP. Approved the final version: JS, SJK, PS, SP. Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JS, SJK, PS, SP.
Funding
The study was supported in part by a Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organization had no role in the design or conduct of this research
Data availability
The datasets analysed during the current study are not publicly available due to use of protected health information but are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets analysed during the current study are not publicly available due to use of protected health information but are available from the corresponding author on reasonable request.