Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Clinical Outcomes of Eyes With Diabetic Macular Edema Switched From Aflibercept to Ranibizumab Therapy

Phoebe L. Mellen, MD; Anthony Obeid, MD, MPH; Turner D. Wibbelsman, BS; Jason Hsu, MD; Michelle A. Konkoly, BS; Michael R. Velez, BA; Daniel B. Calem, BA; Kareem Sioufi, MD; Thomas L. Jenkins, MD; David Xu, MD; Allen Chiang, MD; Omesh P. Gupta, MD; Marc Spirn, MD; Carl D. Regillo, MD; Allen C. Ho, MD; Michael A. Klufas, MD; for the Wills Eye Anti-VEGF (WAVE) Study Group

Abstract

BACKGROUND AND OBJECTIVE:

In 2018, cases of inflammation were reported after intravitreal aflibercept (IVA), which resulted in switches to intravitreal ranibizumab (IVR). The authors' purpose was to evaluate outcomes after switching from IVA to IVR in diabetic macular edema (DME).

PATIENTS AND METHODS:

Retrospective cohort study. Eyes switched from IVA to IVR for treating DME were included. Data were gathered from three visits before to three visits post-switch. Outcome measures included central subfoveal thickness (CFT) and Snellen visual acuity (VA).

RESULTS:

There was a statistically significant increase in CFT at the first visit (325 μm ± 234 μm; P = .006) compared to the switch visit, but no difference later visits (268 μm ± 103 μm; P = .32; 284 μm ± 118 μm; P = .11; n = 54). There was no statistically significant change in mean logarithm of the minimum angle of resolution VA between the switch and later visits (0.43 ± 0.38, P = .95; 0.38 ± 0.30, P = .12; 0.41 ± 0.37, P = .69).

CONCLUSIONS:

The authors observed transient worsening of macular edema in eyes treated for DME when switched from aflibercept to ranibizumab.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:691–697.]

Abstract

BACKGROUND AND OBJECTIVE:

In 2018, cases of inflammation were reported after intravitreal aflibercept (IVA), which resulted in switches to intravitreal ranibizumab (IVR). The authors' purpose was to evaluate outcomes after switching from IVA to IVR in diabetic macular edema (DME).

PATIENTS AND METHODS:

Retrospective cohort study. Eyes switched from IVA to IVR for treating DME were included. Data were gathered from three visits before to three visits post-switch. Outcome measures included central subfoveal thickness (CFT) and Snellen visual acuity (VA).

RESULTS:

There was a statistically significant increase in CFT at the first visit (325 μm ± 234 μm; P = .006) compared to the switch visit, but no difference later visits (268 μm ± 103 μm; P = .32; 284 μm ± 118 μm; P = .11; n = 54). There was no statistically significant change in mean logarithm of the minimum angle of resolution VA between the switch and later visits (0.43 ± 0.38, P = .95; 0.38 ± 0.30, P = .12; 0.41 ± 0.37, P = .69).

CONCLUSIONS:

The authors observed transient worsening of macular edema in eyes treated for DME when switched from aflibercept to ranibizumab.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:691–697.]

Introduction

Diabetic macular edema (DME) is the leading cause of vision loss in patients with diabetes mellitus. During the past 2 decades, the first-line treatment for DME has shifted from focal macular laser photocoagulation to injections of intravitreal anti-vascular endothelial growth factor (VEGF) agents.1 These anti-VEGF agents have shown improved anatomic and functional outcomes when compared to laser therapy.2–4 The three anti-VEGF agents currently used in clinical practice for DME include ranibizumab (Lucentis; Genentech, South San Francisco, CA), aflibercept (Eylea; Regeneron, Tarrytown, NY), and bevacizumab (Avastin; Genentech, South San Francisco, CA), which is off-label for this indication.

The Protocol T trial of the Diabetic Retinopathy Clinical Research (DRCR) network demonstrated superior visual and anatomic outcomes at 12-month follow-up in eyes receiving aflibercept compared to ranibizumab or bevacizumab.5 This led to the widespread adoption of aflibercept in DME treatment. However, 2-year protocol T data showed no difference in visual outcome between ranibizumab and aflibercept.6 In 2017 and 2018, multiple cases of sterile endophthalmitis with aflibercept use occurred in various practices throughout the U.S., a phenomenon initially described back in 2015.7,8 As a result, some physicians opted to switch all patients receiving aflibercept for DME to ranibizumab, which provides unique insight into the effects of such a widespread switch. Herein, we investigate the effects of such a switch in treatment, including changes in anatomic and functional outcomes.

Patients and Methods

This study was approved by the institutional review board of Wills Eye Hospital and was compliant with the Health and Insurance Portability Act of 1996. Patients with a history of DME receiving anti-VEGF therapy with aflibercept were identified using International Classification of Disease 9th and 10th revision and current procedural terminology billing codes. Inclusion criteria included eyes that received at least three consecutive intravitreal aflibercept injections for DME and then switched to ranibizumab therapy between January 2018 and April 2018. Exclusion criteria included a history of neovascular age-related macular degeneration, retinal vein occlusion, uveitis, and a history of vitrectomy, laser photocoagulation, or intravitreal ranibizumab therapy 6 months prior to the switch date. Seven timepoints were analyzed. These included the three consecutive visits just before the switch (third, B3; second, B2; first, B1), the switch visit, and the three consecutive visits post-switch (first, P1; second, P2; third, P3). Eyes were excluded if the intervals between B2 to B1 and B1 to switch visit were greater than 7 days apart, or if the interval between the switch visit and P1 visit was greater than the B1 to switch visit interval.

Clinical Outcomes

Baseline demographic information collected for each patient were age, gender, diabetic retinopathy severity, and HbA1C. Visual acuity (VA) was recorded at all visits using best-available Snellen VA measurements based on either corrected or pinhole vision. Duration between each visit was then measured for comparison purposes.

Anatomic Outcomes

Spectral-domain optical coherence tomography (OCT) outcomes were gathered from each visit if available. Central foveal thickness (CFT) was obtained using the caliper tool built into the software package (Heidelberg Eye Explorer; Heidelberg Engineering, Heidelberg, Germany) measuring the outer border of the internal limiting membrane to the inner border of the retinal pigment epithelium. Additionally, each scan was evaluated for intraretinal and subretinal fluid.

Statistical Analysis

All statistical tests were performed using SPSS Version 24 (IBM Corp., Armonk, NY). VA measurements were converted to the logarithm of the minimum angle of resolution (logMAR) for paired comparisons. Generalized estimating equation was used for outcome comparisons to account for intercorrelation between eyes coming from the same patient. Statistical significance was defined as a P value of less than .05.

Results

A total of 102 eyes from 72 patients were included in the analysis and all received ranibizumab at the switch visit. Baseline characteristics are summarized in Table 1.

Baseline Characteristics of Patients/Eyes With Diabetic Macular Edema Switched From Intravitreal Aflibercept To Intravitreal Ranibizumab

Table 1:

Baseline Characteristics of Patients/Eyes With Diabetic Macular Edema Switched From Intravitreal Aflibercept To Intravitreal Ranibizumab

Mean (± standard deviation) age was 67.5 years (± 9.3; range: 45–92 years). There were 38 (52.8%) males in the cohort. At the P1 visit, eight (7.8%) eyes received no injection, 85 (83.3%) received ranibizumab, and nine (8.8%) were switched back to aflibercept. At the P2 visit, five (4.9%) eyes received no injection, 80 (78.4%) received ranibizumab, and 17 (16.7%) were switched back to aflibercept. The duration between visit dates is summarized in Figure 1. The mean number of days from the B1 visit to the switch visit and switch visit to P1 visit was 44 and 41 days, respectively.

Mean duration between injections three (B3), two (B2), and one (B1) visit before the switch visit, the switch visit, and one (P1), two (P2), and three (P3) visits post-switch. SD = standard deviation

Figure 1.

Mean duration between injections three (B3), two (B2), and one (B1) visit before the switch visit, the switch visit, and one (P1), two (P2), and three (P3) visits post-switch. SD = standard deviation

There was a significant decrease in mean CFT from 286 (± 134) μm at the B3 visit and 284 (± 126) μm at the B2 visit to 262 (± 113) μm at the switch visit (P = .004 [n=100] and P = .008 [n=101], respectively). There was no significant difference in mean CFT at the B1 visit (268 [±107] μm; P = .41; n = 100] when compared to the switch visit. There was a statistically significant increase in mean CFT by 62 μm to 325 (± 234) μm at the P1 visit when compared to the switch visit (P = .006). At the P1 visit, 57 (55.9%) eyes had an increase in CFT, 36 (35.3%) decreased, and nine (8.8%) remained the same. For eyes that received ranibizumab at the P1 visit, there was no significant difference in mean CFT at the P2 visit (268 [± 103] μm; P = .36; n = 84) when compared to the switch visit. In eyes that continued to receive ranibizumab at the P2 visit, no significant change in mean CFT was observed at the P3 visit (284 [± 118] μm; P = .11; n=54) when compared to the switch visit (Figure 2). Overall, there was a decline in the mean follow-up interval (Switch-P1 vs. P1-P2, and P1-P2 vs. P2-P3), but this was not statistically significant (P = .33, P = .75). For eyes that had exact same interval between the B1 and the switch visit and the switch visit to the P1 visit, no significant difference in CFT was seen between the B1 visit (258 [± 101]) and the switch visit (254 [± 101]; P = .36; n = 68). However, there was a significant increase in CFT at the P1 visit (338 [± 269]) compared to the switch visit (P = .008; n = 68). For eyes that had exact same interval between the B1 and the switch visit and the switch visit to the P1 visit, 41 (60.3%) eyes had an increase in CFT, 21 (30.9%) had a decrease in CFT, and six (8.8%) had no change at the P1 visit compared to the switch visit.

Change in central foveal thickness post switch to ranibizumab therapy in eyes previously treated with aflibercept for diabetic macular edema. All P values represent statistical comparisons made to the switch visit.

Figure 2.

Change in central foveal thickness post switch to ranibizumab therapy in eyes previously treated with aflibercept for diabetic macular edema. All P values represent statistical comparisons made to the switch visit.

There was a significant correlation between CFT increase and the duration between the switch visit and the P1 visit (b = 3.7; P = .02). Mean CFT increase by duration is summarized in Figure 3. Eyes that had a P1 interval of 28 days or less had a significantly attenuated increase in CFT at the P1 visit when compared to eyes with an interval of greater than 28 days (8 μm vs. 83 μm; P = .02). There was no significant correlation between change in CFT from the switch visit to the P1 visit and the number of aflibercept injections received prior to the switch visit (P = .29). There was no significant difference in CFT increase at the P1 visit between eyes that remained on ranibizumab and eyes that switched to aflibercept at the P2 visit (68 vs. 119 μm; P = .38). In a subgroup of eyes with no prior history of ranibizumab, a significant increase in mean CFT was found from the switch visit (264 [± 106]) to the P1 visit (317 [± 215]; P = .02; n = 83).

Change in central foveal thickness post switch to ranibizumab therapy in eyes previously treated with aflibercept for diabetic macular edema stratified by duration between the switch and post-switch visit.

Figure 3.

Change in central foveal thickness post switch to ranibizumab therapy in eyes previously treated with aflibercept for diabetic macular edema stratified by duration between the switch and post-switch visit.

There was no significant increase in the amount of intraretinal fluid at the P1 visit (P = .15), the P2 visit (P = .99; n = 84), and the P3 visit (P = .32; n = 54) for eyes that remained on ranibizumab post-switch (Figure 4a). There was no significant increase in the number of eyes with subretinal fluid at the P1 visit (P = .053) and the P2 visit (P = .17; n = 84) for eyes that either remained on ranibizumab post switch (Figure 4b). No eyes demonstrated any subretinal fluid at the P3 visit.

Changes in (A) intraretinal and (B) subretinal fluid prevalence at the switch visit, and the P1, P2, and P3 visits (one visit, two visits, and three visits post-switch, respectively).

Figure 4.

Changes in (A) intraretinal and (B) subretinal fluid prevalence at the switch visit, and the P1, P2, and P3 visits (one visit, two visits, and three visits post-switch, respectively).

There was no significant difference in mean logMAR VA at the B3 (0.43 [± 0.37]; P = .99), B2 (0.43 [± 0.35]; P = .83), and B1 visits (0.40 [± 0.36]; P = .051) when compared to the switch visit (0.43 [±0.36]). There was also no significant difference between the mean logMAR VA at the P1 visit (0.43 [± 0.38]; P = .95) when compared to the switch visit. For eyes that remained on ranibizumab at the P1 visit, no significant difference in mean logMAR VA at the P2 (0.38 [± 0.30]; P = .12; n = 85) visit was observed compared to the switch visit. Similarly, for eyes that received ranibizumab at the P1 and P2 visit, no significant difference in mean logMAR VA was observed at the P3 visit (0.41 [±0.37]; P = .69; n = 55) when compared to the switch visit. There was no significant change in mean logMAR at the P1 visit (0.39 [± 0.29] when compared to the switch visit (0.39 [± 0.31]) for eyes with an equal number of days between the B1 and switch visits and the switch visit to P1 visit (P = .76).

Discussion

In this retrospective study, we observed rapid anatomic changes after switching to ranibizumab for eyes with DME previously receiving intravitreal aflibercept at regular, fixed intervals. Our results also show that there is no significant change in VA over short-term follow-up (mean follow-up: 109 days). Previous studies have evaluated outcomes after switching anti-VEGF therapy.9–12 However, these studies have primarily evaluated a switch in therapy to aflibercept from either bevacizumab or ranibizumab in the setting of persistent macular edema. This is the first study to evaluate the effects of a switch from aflibercept to ranibizumab. Most studies have indicated an anatomic improvement when switching to aflibercept. However, these findings are difficult to validate given the possibility of tachyphylaxis, regression to the mean, and limited follow-up.9 Our results demonstrated a significant, immediate increase in CFT at the time of the switch from aflibercept to ranibizumab. Moreover, we observed relatively stable VA, despite the anatomic worsening on the first post-visit switch.

Although studies on macular thickness changes after switching to ranibizumab from aflibercept therapy are lacking, significant anatomic disparities between the two agents for DME have been observed previously. In a large-scale randomized controlled trial from the DRCR network, eyes receiving aflibercept had a 19-μm greater decrease in central subfield thickness compared to ranibizumab (P = .04) at the 1-year follow-up visit.5 These differences, however, were not observed at the 2-year follow-up visit. Previous switch studies have shown similar changes in macular thickness after initiation of aflibercept for eyes with persistent macular edema.10–12 We observed anatomic worsening immediately upon switching from aflibercept to ranibizumab.

Several potential explanations could account for the observed spike in CFT immediately post-switch. Some degree of greater durability with aflibercept has been suspected based on clinical trends and pharmacokinetic studies. Furthermore, the binding affinity of aflibercept has been shown to be almost 140-times higher than that of ranibizumab using mathematical models.13 Recent studies by Fauser et al.14 have shown that aflibercept has a longer duration of VEGF suppression than ranibizumab when measured in the anterior chamber fluid samples in eyes with neovascular age-related macular degeneration (nAMD). Moreover, in eyes with nAMD, aflibercept suppresses VEGF for an average of 10 weeks,14 compared to an average suppression of 37 days (range: 29–67 days) in eyes receiving ranibizumab.15 This notion is supported by the absence of CFT changes in eyes with follow-up intervals of 28 days or less between the switch and P1 visit. Previously controlled eyes could potentially have been extended to longer intervals without recurrence of fluid on aflibercept. Another explanation is the unique ability of aflibercept to selectively target placental growth factor (PlGF), a molecule associated with diabetic retinopathy.16 However, if this was the primary cause, we would expect sustained worsening of CFT after switching to ranibizumab. It is also important to note that one potential confounder could be progression of the disease. However, the pre-switch trend demonstrated significant improvement in CFT at longer intervals. Therefore, although we cannot be certain that these morphological changes are not at least in part due to disease progression, our findings do suggest that they are to some extent secondary to the switch in anti-VEGF agent.

Our follow-up findings demonstrated that the mean CFT returned to baseline after continuing ranibizumab at the P2 and P3 visits. However, one likely confounder is the decrease in mean follow-up time interval for eyes that remained on ranibizumab. This is likely due to physicians decreasing the injection intervals for those eyes that had worsening edema after the switch.

Despite the anatomic changes observed, there was no significant difference in mean logMAR VA. It is suspected that visual acuity lags behind the reduction in foveal thickness in eyes with DME. Improvement in VA has been seen when treatment is switched to aflibercept from either ranibizumab or bevacizumab at longer follow-up intervals. Moreover, the DRCR Protocol T trial has also shown that eyes with starting VA of 20/50 or worse demonstrate significantly better improvement in vision with aflibercept treatment compared to ranibizumab therapy for DME at year 1 but not at Year 2. Ideally, to identify any long-term functional changes associated with switching from aflibercept to ranibizumab therapy, longer follow-up at identical intervals before and after switching would be required. However, this would prove challenging in a real-world setting, as physicians observing worsening edema would likely decrease injection intervals or switch agents to try to improve the therapeutic effect.

There are several limitations to our study. The most important limitation is the lack of a control arm. A matched control arm would have helped elucidate whether the changes observed were secondary to switch in therapy or disease progression. However, the fixed intervals coupled with the anatomic improvements seen at the visits prior to the switch suggest that the change in therapy may have an important role in anatomic outcomes. Moreover, the circumstances of the switch being related to physician concern about sterile endophthalmitis with aflibercept rather than clinical features of the DME make disease progression a less likely confounder. Our study also lacks long-term follow-up. Long-term follow-up is particularly important in a disease such as DME, where visual changes are often observed over a long period of time.3,5 Future studies will therefore be required to confirm these findings. Finally, selection bias is another limitation that may have affected the outcomes observed in our study. This can be a result of physicians opting to switch back to aflibercept or decreasing injection intervals after witnessing worsening of disease. Future studies that introduce consistent therapy will be required to further establish the role of switching therapy in observed outcomes but remains challenging as mentioned above.

In conclusion, we observed significant worsening of DME in eyes switched to ranibizumab from aflibercept therapy at the first visit following the switch. The short-term worsening in macular edema was significantly correlated with longer pre- and post-switch intervals between injections. However, no significant short-term functional changes were observed. Extended follow-up of eyes that remained on ranibizumab would be helpful to understand the long-term anatomic and functional outcomes.

References

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Baseline Characteristics of Patients/Eyes With Diabetic Macular Edema Switched From Intravitreal Aflibercept To Intravitreal Ranibizumab

Factor Value

Age (Years ± SD) 67.5 (± 9.3)

Gender
  Female 34 (47.2%)
  Male 38 (52.8%)

Eye
  Right 50 (49%)
  Left 52 (51%)

HbA1C (Switch Date) 7.3 (±1.2)

Disease Severity
  Nonproliferative diabetic retinopathy 77 (75.5%)
  Proliferative diabetic retinopathy 25 (24.5%)

Total Number of Injection Prior to Switch Visit (± SD; Range) 14.8 (±11.1; 3–58)

Total Number of Aflibercept Injections Prior to Switch Visit (± SD; Range) 12.7 (±7.9; 3–37)

Lens Status
  Phakic 53 (52.0%)
  Pseudophakic 49 (48.0%)
Authors

From The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, 840 Walnut Street, Suite 1020, Philadelphia, Pennsylvania (PLM, AO, TDW, JH, KS, TLJ, DX, AC, OPG, MS, CDR, ACH, MAK); and Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut St, #100, Philadelphia, Pennsylvania (MAK, MRV, DBC).

Presented at the American Society of Retina Specialists Annual Meeting, Chicago, in July 2019.

Dr. Hsu has received grants from Roche/Genentech and Santen, as well as grants and personal fees from Ophthotech, outside the submitted work. Dr. Chiang has received grants from Roche/Genentech and Regeneron outside the submitted work. Dr. Regillo has received grants from Roche/Genentech, Regeneron, Allergan, Novartis, and Iconic, as well as consulting fees from Genentech, Alcon, Allergan, Iconic, Notal Vision, Kodiak, Santen, Shire, and Novartis. Dr. Ho has received grants from Alcon, Allergan, Genentech, Novartis, and Regeneron, and is a consultant for Alcon, Allergan, Genentech, Novartis, and Regeneron. Dr. Klufas has received personal fees from Genentech, Regeneron, and Allergan outside the submitted work. He is a consultant for Allergan and Novartis and a speaker and consultant for Roche/Genentech. The remaining authors report no relevant financial disclosures.

Address correspondence to Michael A. Klufas, MD, Retina Service, Wills Eye Hospital, Suite 1020, 840 Walnut Street, Philadelphia, PA 19107; email: mklufas@midatlanticretina.com.

Received: April 27, 2020
Accepted: October 07, 2020

10.3928/23258160-20201202-03

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