RESPONSE TO AFLIBERCEPT AS SECONDARY THERAPY IN PATIENTS WITH PERSISTENT RETINAL EDEMA DUE TO CENTRAL RETINAL VEIN OCCLUSION INITIALLY TREATED WITH BEVACIZUMAB OR RANIBIZUMAB JAMES A. EADIE, MD, MICHAEL S. IP, MD, AMOL D. KULKARNI, MD Background: Recent advances have given practitioners options for the treatment of macular edema secondary to central retinal vein occlusion. These options include steroid injections and implants as well as anti-vascular endothelial growth factor medications. However, there is little in the medical literature to guide secondary therapy when an initial treatment strategy is insufficient. The authors present encouraging results from the treatment of six consecutive cases of central retinal vein occlusion treated with aflibercept as a secondary therapy for macular edema refractory to repeated intravitreal bevacizumab or ranibizumab injections. Methods: A retrospective review of six consecutive cases of central retinal vein occlusion with persistent macular edema despite regular anti-vascular endothelial growth factor injections that were transitioned to aflibercept was conducted. Optical coherence tomography and visual acuity data were examined. Results: All six eyes from the six patients included showed either complete or near complete resolution of macular edema with one or two injections of aflibercept. The improvement in edema was accompanied by lasting modest visual gains in three of the six patients and in subjective visual improvement in four of the six patients. Conclusion: The six eyes in this series all responded favorably to aflibercept as a secondary therapy. Although the sample size is too small to draw definitive conclusions, the results are encouraging. RETINA 34:2439–2443, 2014
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edema secondary to CRVO. The SCORE and GENEVA trials evaluated the use of corticosteroid injections and implants, respectively, whereas the CRUISE and COPERNICUS trials evaluated ranibizumab and aflibercept, both primarily anti-vascular endothelial growth factor agents. In addition, many practitioners use bevacizumab off-label for this condition. There are numerous studies with level 2 and level 3 evidence demonstrating the safety and efficacy of bevacizumab for CRVO.5–7 At present, anti-vascular endothelial growth factor (VEGF) therapy is the most commonly used primary therapy because of the perceived superior safety profile (less cataract and intraocular pressure elevation) compared with corticosteroid therapy.
ecent advances have given practitioners multiple options for the treatment of macular edema due to central retinal vein occlusion (CRVO). These options include intravitreal corticosteroid injections, corticosteroid implants, and anti-vascular endothelial growth factor agents. The SCORE,1 GENEVA,2 CRUISE,3 and now COPERNICUS4 trials indicate that all of these options have benefit to patients with macular From the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisonsin. M. S. Ip is a consultant for Regeneron, Genentech, Allergan, Thrombogenics, and Valeant. The other authors have no financial/ conflicting interests to disclose. Reprint requests: James A. Eadie, MD, 2880 University Avenue, Madison, WI 53703; e-mail: [email protected]
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2440 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 12
in the authors’ experience, it does not tend to alter their management. Six eyes of the six consecutive patients who presented with persistent edema after repeated anti-VEGF injections (ranibizumab and/or bevacizumab) were examined. The persistent retinal edema secondary to CRVO was demonstrated on OCT imaging. Each eye had a minimum of 10 monthly injections of bevacizumab or ranibizumab. As a result of this persistent edema, each patient was transitioned to aflibercept therapy. The patients in this series were treated conservatively with injections every 4 weeks to 6 weeks initially. Two patients were being treated less frequently at the time of transition because of minimal response in one patient and frequent cancellations in another. These patients were initially treated with regular injections and responded suboptimally. Repeat OCT and visual acuity data were performed after the transition to aflibercept and compared with the data collected before the transition. The patients were followed for a minimum of 3 months after transition (range, 3–9 months). Dosing schedules were maintained at 4- to 6-week intervals after transition to aflibercept.
The COPERNICUS trial examined the efficacy of aflibercept, the newest intravitreal therapy available, and showed a benefit regarding final visual outcome and retinal thickness over sham treatment.4 Pharmacodynamics studies indicate that aflibercept has a higher binding affinity for VEGF than either bevacizumab or ranibizumab.8 In addition, aflibercept has activity against VEGF-B and placental-derived growth factor in addition to VEGF-A.9 Although there are no studies that directly compare aflibercept with the other modalities of treatment for CRVO, this higher binding affinity and broader spectrum of activity suggest a possible advantage of aflibercept over the other anti-VEGF treatments. We present encouraging results from the treatment of six consecutive cases of CRVO treated with aflibercept as a secondary therapy for macular edema refractory to repeated intravitreal bevacizumab or ranibizumab injections.
Methods After obtaining expedited approval from the University of Wisconsin Institutional Review Board, patient information including demographics, visual acuity, central retinal thickness on optical coherence tomography (OCT), and number of intravitreal injections were retrospectively gathered. Fluorescein angiography was not performed on these patients because,
Results Six eyes of the six consecutive patients from a single provider, MI, treated for macular edema secondary to
Table 1. Case 1 Age, years 77 Sex Female Eye OD Acuity at 20/200 presentation No. of injections 20 pre-aflibercept bevacizumab Acuity at transition 20/300 Acuity post20/250 aflibercept Acuity at the last 20/125 examination Thickness pre545 aflibercept, mm Thickness post133 aflibercept, mm Thickness at the last 252 examination, mm Length of follow-up 8 after transition, months Trace edema Optical coherence tomographic morphology at the last examination
Case 2
Case 3
Case 4
Case 5
Case 6
62 Male OS 20/400
74 Male OD 20/30
71 Male OS 20/40
66 Male OD 7/200
78 Male OD 20/70
16 bevacizumab 20/150 20/100
28 ranubizumab 20/40 20/50
10 bevacizumab 20/40 20/30
12 Avastin, 3 Luscentis 20/200 20/200
18 bevacizumab 20/60 20/50
20/125
20/50
20/40
8/200
20/40
784
392
483
344
595
120
272
332
217
176
105
307
292
282
165
9
8
8
6.5
3
Dry
Central cysts
Dry
Trace edema
Trace edema
AFLIBERCEPT FOR PERSISTENT EDEMA IN CRVO EADIE ET AL
CRVO with persistent edema on OCT despite regular anti-VEGF treatment with bevacizumab or ranibizumab were identified. The majority of these patients (5/6) had visual acuity better than 20/400 at their initial presentation. These patients were given intravitreal aflibercept injections as secondary therapy. Visual acuity and OCT images were examined before and 1 month to 2 months after treatment with aflibercept. Data from the most recent follow-up appointment were also analyzed. The mean pre-aflibercept OCT thickness at the center point was 524 mm. One month after injection, this thickness decreased to a mean of 208 mm. At their most recent follow-up visit (minimum 3 months after transition), the average thickness was 234 mm (Table 1 and Figure 1). All six eyes had a reduction in the amount of macular edema on OCT. One patient did have a recurrence of edema when extended beyond 5 weeks. Lasting modest visual acuity improvements were seen in three of the six patients. Four of the six patients experienced a subjective improvement of visual acuity in addition to improvement on OCT. The average number of anti-VEGF injections before
2441
the transition to aflibercept was 17.8 (range, 10–28). These data are summarized in Table 1. Pre- and postaflibercept OCT images for the first 4 patients are shown in Figure 2. The patient with the worst visual outcome (Case 5) had a distinct loss of retinal architecture including outer retinal bands, before transition, which may account for the lack of improvement in visual acuity objectively and subjectively.
Discussion There are now multiple treatment modalities for macular edema secondary to CRVO with good evidence to support the use of these therapies. The clinical trials that support the use of these therapies compare each treatment to sham1–4 rather than to each other. There is little in the medical literature that compares one treatment modality to another. Xiaoyan et al published a series of 31 consecutive CRVO cases randomized to receive bevacizumab or triamcinolone. They showed no statistical difference in macular thickness
Fig. 1. Pre-aflibercept optical coherence tomographic images in the left column with the corresponding post-aflibercept optical coherence tomographic images on the right.
2442 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 12
Fig. 2. Central neurosensory retina thickness pre-aflibercept, post-aflbercept, and at last follow-up.
or best-corrected visual acuity between the two groups in this small series.10 Similarly, Mayer et al11 found no difference in best-corrected visual acuity in patients with CRVO who were treated with dexamethasone implant monotherapy versus three loading doses of bevacizumab followed by dexamethasone implant. When a given treatment fails, there is little evidence to guide practitioners as to what is an appropriate second-line therapy. The six eyes in this series all responded to aflibercept as a secondary therapy. Although the sample size is too small to draw definitive conclusions, the results are encouraging. All six eyes had reduction of retinal thickness, if not total resolution of macular edema, on OCT imaging with one injection. These gains were relatively preserved as patients were continued on this treatment, although some trace exudation persisted in four of the six patients. Subjective improvement was noted in four of the six patients. Three patients noted immediate subjective improvement in vision, whereas one noted an improvement after three injections of aflibercept. This suggests that aflibercept may be a viable treatment option in patients who do not have an optimal response to initial therapy with bevacizumab or ranibizumab. This study has several inherent weaknesses. This is a retrospective study. Although the cases are consecutive, it is possible that the treating physician did not use aflibercept as a secondary therapy in some eyes felt likely to be refractory to any second-line therapy, resulting in ascertainment bias. The follow-up data for these patients are limited in length, ranging from 3 months to 9 months after therapeutic transition. It is not clear whether tachyphylaxis to aflibercept will develop. Additionally, not all eyes were treated with
the same dosing schedule before the transition to aflibercept. Most of the eyes were treated with bevacizumab and/or ranibizumab using a treat and extend regimen so that the dosing schedule was variable before the transition. Ideally, all eyes would have been treated with bevacizumab and/or ranibizumab on a monthly schedule, for a minimum number of injections before transitioning to aflibercept. Despite the shortcomings described above, the initial responses to aflibercept in these patients are encouraging. In each case, there was a rapid reduction in OCT measured retinal thickness and modest subjective and objective improvement in visual acuity in a patient population that was deemed refractory to initial therapy with bevacizumab and/or ranibizumab. Further studies are needed to determine if these results can be replicated. Key words: CRVO, aflibercept, macular edema, intravitreal pharmacotherapy. References 1. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:1101–1114. 2. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146. 3. Brown DM, Campochiaro PA, Singh RP, et al. Ranubizumab for macular edema following central retinal vein occlusion: sixmonth primary end point results of a phase III study. Ophthalmology 2010;117:1124–1133.e1.
AFLIBERCEPT FOR PERSISTENT EDEMA IN CRVO EADIE ET AL 4. Brown DM, Heier J, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol 2013;155:429–437. 5. Spaide R, Chang L, Klancnik J, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. AM J Ophthalmol 2009;147:298–306. 6. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol 2009;93:452–456. 7. Zhang H, Liu Z, Sun P, et al. Intravitreal bevacizumab for treatment of macular edema secondary to retinal vein occlusion: eighteen-month results of a prospective trial. J Ocul Pharmacol Ther 2011;27:615–621.
2443
8. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranubizumab and bevacizumab. Angiogenesis 2012;15:171–185. 9. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393–11398. 10. Xiaoyan D, Jianqing L, Xuting H, et al. Prospective study of intravitreal triamcinolone acetonide versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina 2011;31:838–845. 11. Mayer W, Remy M, Wolf A, et al. Comparison of intravitreal bevacizumab upload followed by a dexamethasone implant versus dexamethasone implant monotherapy for retinal vein occlusion with macular edema. Ophthalmologica 2012;228: 110–116.
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edema secondary to CRVO. The SCORE and GENEVA trials evaluated the use of corticosteroid injections and implants, respectively, whereas the CRUISE and COPERNICUS trials evaluated ranibizumab and aflibercept, both primarily anti-vascular endothelial growth factor agents. In addition, many practitioners use bevacizumab off-label for this condition. There are numerous studies with level 2 and level 3 evidence demonstrating the safety and efficacy of bevacizumab for CRVO.5–7 At present, anti-vascular endothelial growth factor (VEGF) therapy is the most commonly used primary therapy because of the perceived superior safety profile (less cataract and intraocular pressure elevation) compared with corticosteroid therapy.
ecent advances have given practitioners multiple options for the treatment of macular edema due to central retinal vein occlusion (CRVO). These options include intravitreal corticosteroid injections, corticosteroid implants, and anti-vascular endothelial growth factor agents. The SCORE,1 GENEVA,2 CRUISE,3 and now COPERNICUS4 trials indicate that all of these options have benefit to patients with macular From the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisonsin. M. S. Ip is a consultant for Regeneron, Genentech, Allergan, Thrombogenics, and Valeant. The other authors have no financial/ conflicting interests to disclose. Reprint requests: James A. Eadie, MD, 2880 University Avenue, Madison, WI 53703; e-mail: [email protected]
2439
2440 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 12
in the authors’ experience, it does not tend to alter their management. Six eyes of the six consecutive patients who presented with persistent edema after repeated anti-VEGF injections (ranibizumab and/or bevacizumab) were examined. The persistent retinal edema secondary to CRVO was demonstrated on OCT imaging. Each eye had a minimum of 10 monthly injections of bevacizumab or ranibizumab. As a result of this persistent edema, each patient was transitioned to aflibercept therapy. The patients in this series were treated conservatively with injections every 4 weeks to 6 weeks initially. Two patients were being treated less frequently at the time of transition because of minimal response in one patient and frequent cancellations in another. These patients were initially treated with regular injections and responded suboptimally. Repeat OCT and visual acuity data were performed after the transition to aflibercept and compared with the data collected before the transition. The patients were followed for a minimum of 3 months after transition (range, 3–9 months). Dosing schedules were maintained at 4- to 6-week intervals after transition to aflibercept.
The COPERNICUS trial examined the efficacy of aflibercept, the newest intravitreal therapy available, and showed a benefit regarding final visual outcome and retinal thickness over sham treatment.4 Pharmacodynamics studies indicate that aflibercept has a higher binding affinity for VEGF than either bevacizumab or ranibizumab.8 In addition, aflibercept has activity against VEGF-B and placental-derived growth factor in addition to VEGF-A.9 Although there are no studies that directly compare aflibercept with the other modalities of treatment for CRVO, this higher binding affinity and broader spectrum of activity suggest a possible advantage of aflibercept over the other anti-VEGF treatments. We present encouraging results from the treatment of six consecutive cases of CRVO treated with aflibercept as a secondary therapy for macular edema refractory to repeated intravitreal bevacizumab or ranibizumab injections.
Methods After obtaining expedited approval from the University of Wisconsin Institutional Review Board, patient information including demographics, visual acuity, central retinal thickness on optical coherence tomography (OCT), and number of intravitreal injections were retrospectively gathered. Fluorescein angiography was not performed on these patients because,
Results Six eyes of the six consecutive patients from a single provider, MI, treated for macular edema secondary to
Table 1. Case 1 Age, years 77 Sex Female Eye OD Acuity at 20/200 presentation No. of injections 20 pre-aflibercept bevacizumab Acuity at transition 20/300 Acuity post20/250 aflibercept Acuity at the last 20/125 examination Thickness pre545 aflibercept, mm Thickness post133 aflibercept, mm Thickness at the last 252 examination, mm Length of follow-up 8 after transition, months Trace edema Optical coherence tomographic morphology at the last examination
Case 2
Case 3
Case 4
Case 5
Case 6
62 Male OS 20/400
74 Male OD 20/30
71 Male OS 20/40
66 Male OD 7/200
78 Male OD 20/70
16 bevacizumab 20/150 20/100
28 ranubizumab 20/40 20/50
10 bevacizumab 20/40 20/30
12 Avastin, 3 Luscentis 20/200 20/200
18 bevacizumab 20/60 20/50
20/125
20/50
20/40
8/200
20/40
784
392
483
344
595
120
272
332
217
176
105
307
292
282
165
9
8
8
6.5
3
Dry
Central cysts
Dry
Trace edema
Trace edema
AFLIBERCEPT FOR PERSISTENT EDEMA IN CRVO EADIE ET AL
CRVO with persistent edema on OCT despite regular anti-VEGF treatment with bevacizumab or ranibizumab were identified. The majority of these patients (5/6) had visual acuity better than 20/400 at their initial presentation. These patients were given intravitreal aflibercept injections as secondary therapy. Visual acuity and OCT images were examined before and 1 month to 2 months after treatment with aflibercept. Data from the most recent follow-up appointment were also analyzed. The mean pre-aflibercept OCT thickness at the center point was 524 mm. One month after injection, this thickness decreased to a mean of 208 mm. At their most recent follow-up visit (minimum 3 months after transition), the average thickness was 234 mm (Table 1 and Figure 1). All six eyes had a reduction in the amount of macular edema on OCT. One patient did have a recurrence of edema when extended beyond 5 weeks. Lasting modest visual acuity improvements were seen in three of the six patients. Four of the six patients experienced a subjective improvement of visual acuity in addition to improvement on OCT. The average number of anti-VEGF injections before
2441
the transition to aflibercept was 17.8 (range, 10–28). These data are summarized in Table 1. Pre- and postaflibercept OCT images for the first 4 patients are shown in Figure 2. The patient with the worst visual outcome (Case 5) had a distinct loss of retinal architecture including outer retinal bands, before transition, which may account for the lack of improvement in visual acuity objectively and subjectively.
Discussion There are now multiple treatment modalities for macular edema secondary to CRVO with good evidence to support the use of these therapies. The clinical trials that support the use of these therapies compare each treatment to sham1–4 rather than to each other. There is little in the medical literature that compares one treatment modality to another. Xiaoyan et al published a series of 31 consecutive CRVO cases randomized to receive bevacizumab or triamcinolone. They showed no statistical difference in macular thickness
Fig. 1. Pre-aflibercept optical coherence tomographic images in the left column with the corresponding post-aflibercept optical coherence tomographic images on the right.
2442 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 12
Fig. 2. Central neurosensory retina thickness pre-aflibercept, post-aflbercept, and at last follow-up.
or best-corrected visual acuity between the two groups in this small series.10 Similarly, Mayer et al11 found no difference in best-corrected visual acuity in patients with CRVO who were treated with dexamethasone implant monotherapy versus three loading doses of bevacizumab followed by dexamethasone implant. When a given treatment fails, there is little evidence to guide practitioners as to what is an appropriate second-line therapy. The six eyes in this series all responded to aflibercept as a secondary therapy. Although the sample size is too small to draw definitive conclusions, the results are encouraging. All six eyes had reduction of retinal thickness, if not total resolution of macular edema, on OCT imaging with one injection. These gains were relatively preserved as patients were continued on this treatment, although some trace exudation persisted in four of the six patients. Subjective improvement was noted in four of the six patients. Three patients noted immediate subjective improvement in vision, whereas one noted an improvement after three injections of aflibercept. This suggests that aflibercept may be a viable treatment option in patients who do not have an optimal response to initial therapy with bevacizumab or ranibizumab. This study has several inherent weaknesses. This is a retrospective study. Although the cases are consecutive, it is possible that the treating physician did not use aflibercept as a secondary therapy in some eyes felt likely to be refractory to any second-line therapy, resulting in ascertainment bias. The follow-up data for these patients are limited in length, ranging from 3 months to 9 months after therapeutic transition. It is not clear whether tachyphylaxis to aflibercept will develop. Additionally, not all eyes were treated with
the same dosing schedule before the transition to aflibercept. Most of the eyes were treated with bevacizumab and/or ranibizumab using a treat and extend regimen so that the dosing schedule was variable before the transition. Ideally, all eyes would have been treated with bevacizumab and/or ranibizumab on a monthly schedule, for a minimum number of injections before transitioning to aflibercept. Despite the shortcomings described above, the initial responses to aflibercept in these patients are encouraging. In each case, there was a rapid reduction in OCT measured retinal thickness and modest subjective and objective improvement in visual acuity in a patient population that was deemed refractory to initial therapy with bevacizumab and/or ranibizumab. Further studies are needed to determine if these results can be replicated. Key words: CRVO, aflibercept, macular edema, intravitreal pharmacotherapy. References 1. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:1101–1114. 2. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146. 3. Brown DM, Campochiaro PA, Singh RP, et al. Ranubizumab for macular edema following central retinal vein occlusion: sixmonth primary end point results of a phase III study. Ophthalmology 2010;117:1124–1133.e1.
AFLIBERCEPT FOR PERSISTENT EDEMA IN CRVO EADIE ET AL 4. Brown DM, Heier J, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol 2013;155:429–437. 5. Spaide R, Chang L, Klancnik J, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. AM J Ophthalmol 2009;147:298–306. 6. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol 2009;93:452–456. 7. Zhang H, Liu Z, Sun P, et al. Intravitreal bevacizumab for treatment of macular edema secondary to retinal vein occlusion: eighteen-month results of a prospective trial. J Ocul Pharmacol Ther 2011;27:615–621.
2443
8. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranubizumab and bevacizumab. Angiogenesis 2012;15:171–185. 9. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393–11398. 10. Xiaoyan D, Jianqing L, Xuting H, et al. Prospective study of intravitreal triamcinolone acetonide versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina 2011;31:838–845. 11. Mayer W, Remy M, Wolf A, et al. Comparison of intravitreal bevacizumab upload followed by a dexamethasone implant versus dexamethasone implant monotherapy for retinal vein occlusion with macular edema. Ophthalmologica 2012;228: 110–116.
