- Email: [email protected]
Aflibercept Therapy for Exudative Age-related Macular Degeneration Resistant to Bevacizumab and Ranibizumab
Aflibercept Therapy for Exudative Age-related Macular Degeneration Resistant to Bevacizumab and Ranibizumab BENJAMIN BAKALL, JAMES C. FOLK, H. CULVER BOLDT, ELLIOTT H. SOHN, EDWIN M. STONE, STEPHEN R. RUSSELL, AND VINIT B. MAHAJAN
PURPOSE:
To evaluate the outcome of intravitreal injection of aflibercept in cases with exudative agerelated macular degeneration, (AMD) resistant to injections of bevacizumab or ranibizumab. DESIGN: Retrospective observational case series. METHODS: A retrospective chart review at a single institution was conducted to identify patients with exudative AMD and choroidal neovascularization (CNV) in 1 or both eyes resistant to treatment with ranibizumab or bevacizumab who were switched to treatment with at least 3 monthly injections of aflibercept. In total, 36 eyes from 31 patients were included. The demographic data, visual acuities, central macular thickness on optical coherence tomography (OCT), complications, and number of injections were reviewed. RESULTS: The mean patient age was 79 years (range 60-88). There were 13 male and 18 female patients. The number of prior injections with either bevacizumab or ranibizumab ranged from 6-74. After 3 monthly injections of aflibercept, there was a reduction of either subretinal or intraretinal fluid in 18 of 36 (50.0%) of the treated eyes; the amount of fluid remained stable in 15 eyes (41.7%) and worsened in 3 eyes (8.3%). A significant average decrease was observed for the central macular thickness after 3 injections of 65 mm (P [ 2.9 3 10-6), with no significant change in visual acuity. CONCLUSIONS: Aflibercept therapy appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intraretinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab. (Am J Ophthalmol 2013;-:-–-. Ó 2013 by Elsevier Inc. All rights reserved.)
A
GE-RELATED MACULAR DEGENERATION (AMD) IS
the most common cause of irreversible blindness in the industrialized world. Two landmark clinical trials using intravitreal injections of the humanized monoclonal antibody fragment ranibizumab (Lucentis) in eyes
Accepted for publication Feb 24, 2013. From the Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals & Clinics (B.B., J.C.F., H.C.B., E.H.S., E.M.S., S.R.R., V.B.M.); and Omics Laboratory, The University of Iowa (V.B.M.), Iowa City, Iowa. Inquiries to Vinit B. Mahajan, Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.02.017
Ó
2013 BY
with new-onset neovascular AMD showed that over 90% of treated eyes lost fewer than 15 letters after 24 months of follow-up and the visual acuity could be improved in 33.3%-40%.1,2 This improvement was associated with the drug’s ability to reduce intraretinal edema, subretinal fluid, and hemorrhage. A recent randomized, multicenter, 2-year clinical trial sponsored by the National Institutes of Health revealed that bevacizumab, a humanized murine antibody to vascular endothelial growth factor (VEGF), was noninferior compared with ranibizumab for the treatment of exudative AMD.3 Bevacizumab and ranibizumab injections have had a significant impact on preserving vision and preventing blindness.4 Some patients, however, have a good initial response with resolution of fluid, but then later become resistant to further treatment and develop recurrent exudation with vision loss.5,6 The mechanism of this resistance to treatment with these drugs is not known, but one possibility is tolerance or tachyphylaxis, manifested by a decreased response over time to repeated treatment with a medication.7 Tachyphylaxis sometimes can be reversed by increasing the dose or halting therapy for a period of time before reinstating the same treatment.8 Tachyphylaxis has been suggested in patients treated for exudative AMD.7 Some eyes have shown better resolution of fluid after switching anti-VEGF treatment.9 Tachyphylaxis has been proposed for a number of other treatments, including brimonidine and infliximab.10,11 In a study performed at the National Eye Institute, Forooghian and associates observed 6 eyes that developed tachyphylaxis after repeated bevacizumab injections.6 Gasperini and associates reported a significant decrease of subretinal fluid in the majority of tachyphylactic patients after switching treatments from either ranibizumab or bevacizumab to the other medication. The study showed that 81% of the patients responded favorably after changing intravitreal injection medication.9 Aflibercept is a novel VEGF inhibitor, with a high affinity for VEGF. It is a protein constructed by fusion of the second binding domain of the receptor VEGFR1 and the third binding domain of the receptor VEGFR2 to the crystalline portion of IgG1.12 This has resulted in aflibercept’s having a significantly higher affinity in vitro to VEGF compared with both bevacizumab and ranibizumab13 The intravitreal half-life of aflibercept is 4.7 days in rabbit eyes, which is longer than ranibizumab (2.9 days) and
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
comparable with bevacizumab (4.3 days). The combined high affinity and longer half-life has led to a calculated duration of effect of a single intravitreal injection of 2 mg aflibercept of 48-83 days.13,14 Monthly treatment with aflibercept has been shown to improve the vision in exudative AMD in 2 clinical trials. The treatment with 3 initial monthly injections of 2 mg aflibercept, followed by injections every 8 weeks, has been shown to be noninferior compared with monthly treatments with either aflibercept or ranibizumab.15 Bevacizumab is a humanized murine antibody to VEGF and ranibizumab is a humanized antigen-binding fragment to VEGF, whereas aflibercept is a fusion protein receptor with much higher binding affinity to VEGF than both bevacizumab and ranibizumab. Therefore, an important question is whether eyes that have become resistant to anti-VEGF molecules respond to aflibercept injections. The purpose of this study is to help answer this question by reporting on an initial cohort of eyes that became resistant to treatment with bevacizumab or ranibizumab and then were switched to injections of aflibercept.
METHODS A RETROSPECTIVE OBSERVATIONAL CASE SERIES WAS
performed to study the outcome in eyes with exudative AMD, resistant to the treatment of monthly injections with bevacizumab or ranibizumab, that were switched to at least 3 monthly injections of aflibercept therapy. A written consent was obtained from the patients prior to each injection treatment. The Institutional Review Board for human subjects research at the University of Iowa approved the study protocol for human subjects. The study was compliant with HIPAA (the Health Insurance Portability and Accountability Act of 1996) and adhered to the tenets of the Declaration of Helsinki. Charts were reviewed for patients treated in the Vitreoretinal Clinic at the University of Iowa Department of Ophthalmology and Visual Sciences. Intravitreal injections were performed using the same procedure in all patients, as previously described.16 Inclusion criteria were age >60 years and a diagnosis of exudative AMD, including presence of drusen, as well as pigment epithelial changes in combination with choroidal neovascularization, confirmed by fluorescein angiogram and optical coherence tomography (OCT) at the initial clinic visit. The criteria also included only eyes that had been previously injected with either 1.25 mg bevacizumab or 0.5 mg ranibizumab (Avastin and Lucentis, respectively; Genentech Inc, San Francisco, California, USA) and had an initial response (decrease of retinal edema and subretinal fluid), followed by a recurrent increase or persistent subretinal fluid or retinal edema on OCT. The intraretinal or subretinal fluid had to be present for a minimum of 3 months prior to the first aflibercept 2
injection. This fluid had to be refractory to continued monthly intravitreal injections with the same drug or a change from either bevacizumab or ranibizumab to the other drug with 3 monthly injections administered the 3 months prior to the first aflibercept injection. The criteria for treatment with aflibercept were the same as retreatment criteria for bevacizumab or ranibizumab regarding presence of intraretinal or subretinal fluid. Finally, the last criterion was that at least 3 initial 2-mg aflibercept injections every 4-6 weeks had been administered, followed by a visit within 4-8 weeks after the third aflibercept injection. Patient charts were reviewed until 6 months after the first aflibercept injection. At each visit the visual acuity was measured using a standardized Snellen chart and a comprehensive eye examination, and OCT imaging was performed using Spectralis OCT (Heidelberg Engineering, Carlsbad, California, USA) or Cirrus HD-OCT (Carl Zeiss Meditech, Dublin, California, USA). With Spectralis, 20 3 15degree volume scans containing 19 sections separated by 240 mm were used. The scans were acquired in highspeed mode. The central macular thickness (CMT) was equivalent according to the distance between the 2 algorithm lines. The Spectralis algorithm for placement of the segmentation line in an OCT with a vascular pigment epithelial detachment (PED) has been demonstrated to exhibit a significant difference compared with manual measurement of the CMT.17 Therefore, the CMT, central retinal thickness (CRT), and PED were also measured using the caliper function for the section corresponding to the foveal depression. CMT was measured from the foveal depression to the Bruch membrane; alternatively, where the PED obscured the outer retinal structures, it was measured to the estimated location of the Bruch membrane. CRT was measured from the foveal depression to the inner part of the PED along the CMT measurement line. The PED was calculated as the difference between the CMT and the CRT. The same numerical scan for each individual was analyzed at the different time points. With Cirrus, the 512 3 128 scan pattern was performed consisting of 128 horizontal lines of 512 A-scans per line. The collected demographic data included patient age; sex; laterality of the treated eye; number of ranibizumab, bevacizumab, and aflibercept injections; the time between injections; and the response to treatment as determined by the OCT and visual acuity. The CMT on OCT measurements were collected from the visit of the first treatment visit with aflibercept and until 6 months after the first aflibercept injection. An assessment of the OCT appearance was performed for the images from the selected follow-up visits and compared with the OCT from the visit of the first aflibercept injection. A definite (qualitative visible) change in macular thickness or subretinal or intraretinal fluid was graded as improved, stable, or worsened, similarly as performed in a previously published study of the OCT response after switching anti-VEGF treatment.9 The visual acuity was collected from the first visit of any anti-VEGF
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injection, at the visit of the first aflibercept injection, at the visit after the third injection, and at the visit 6 months after the first aflibercept injection. The Snellen visual acuity was converted to logMAR units. Measurements for the eyes with a change in treatment regimen or eyes that were lostto follow-up after the third injection, but before the 6-month visit, were not included in data collection for the 6-month visit. The occurrence of any severe postoperative complications, including infection, inflammation, arteriothrombotic events, or death within the 6 months after the first aflibercept injection was recorded. The significance of the difference of group means was tested with Student t test (2-tailed, equal variance).
RESULTS A TOTAL OF 36 EYES FROM 31 PATIENTS MET THE INCLUSION
criteria. The mean patient age was 79 years (range 60-88). There were 13 men and 18 women. Of the 36 eyes, 22 were the right eye and 14 were the left eye. The study eyes had received an average of 25.6 injections (range 6-74) prior to treatment with aflibercept, with a mean of 15.5 bevacizumab and 12.8 ranibizumab treatments. Thirty-two eyes had at least 1 trial of switching between bevacizumab and ranibizumab during the period from the first anti-VEGF injection until the first aflibercept treatment, whereas 3 eyes received only bevacizumab and 1 eye received only ranibizumab (Table 1). During the 6 months just prior to the change of treatment, an average of 5.2 injections (range 4-6) had been administered to the study eye. All eyes had received a series of 3 aflibercept injections given 4-6 weeks apart and the interval thereafter was extended at the discretion of the treating retina specialist. All 36 eyes had data collected for the visit after the third aflibercept injection. There were 27 eyes that continued aflibercept injections until at least 6 months after the first injection. The aflibercept treatment was stopped in 9 eyes prior to 6 months after the first injection. Four eyes in 4 patients were switched because of patient co-pay cost after the fifth injection, including 1 eye that in addition had increased subretinal fluid and worsened vision; 1 eye in 1 patient was lost to follow-up since the patient switched providers after the fifth injection; 1 patient was hospitalized after the fifth injection because of renal failure and was unable to return to the clinic for continued injections in the studied eye; 1 eye was treated with photodynamic therapy after the fourth injection because of persistent subretinal fluid; 1 eye had a change in treatment after the fifth injection because of patient preference; and 1 eye developed endophthalmitis after the fifth injection with coagulase-negative Streptococcus. The infected eye underwent vitrectomy and antibiotic injections, with the vision subsequently returning to 20/40, same as prior to the onset of aflibercept injections. VOL. -, NO. -
The manually measured, average CMT for the OCT at the time of switching therapies was 410 mm (range 1741027, median 387). The average CMT at the visit after the third aflibercept injection was 346 mm (range 155784, median 315), and after 6 months the average CMT was 296 mm (range 151-528, median 282). Compared with the CMT at the initial visit, there was a significant decrease in CMT after 3 months of 65 mm (P ¼ 2.9 3 10-6) and after 6 months of 87 mm (P ¼ 5.2 3 10-6) (Table 1). This suggests that aflibercept therapy improved CMT in previously unresponsive eyes. Using the standard Spectralis algorithm, the mean CMT on OCT prior to the first injection of aflibercept was 358 mm (range 181-579, median 335). The average CMT at the first visit after the third injection was 309 mm (range 162-623, median 274) and after 6 months was 298 mm (range 168-561, median 224). Compared with the visit at the first aflibercept injection, there was a significant average decrease in CMT after 3 injections of 48 mm (P ¼ 1.6 3 10-4) and a decrease of 60 mm (P ¼ 9.1 3 10-6) after 6 injections. In 28 of the 36 eyes, a PED was observed at the visit of the first aflibercept injection. Manual measurement of the CRT and calculation of the PED were performed in the 28 eyes with a PED. At the visit for the first aflibercept injection, the average CRT was 295 mm, significantly decreasing by 45 mm, to 250 mm (P ¼ 2.0 3 10-6), at 3 months and decreasing by 77 mm, to 220 mm (P ¼ 1.1 3 10-5), at 6 months. The average PED was 153 mm at the switch, decreasing by 26 mm (P ¼ .015), to 127 mm, at 3 months and decreasing by 13 mm (P ¼ .14), to 101 mm, after 6 months (Table 2). This indicates that aflibercept therapy reduced PED thickness after 3 months, but there were great fluctuations for the eyes observed at 6 months. The mean logMAR Snellen visual acuity at the visit of the first injection with either bevacizumab or ranibizumab was 0.36, which decreased to 0.45 (P ¼ .07) at the visit of the first aflibercept injection. After 3 injections, the average vision was 0.52 (P ¼ .052) and after 6 months the vision was 0.50 (P ¼ .36), which was not significantly changed. After 3 injections, 8 of 36 eyes had 1-2 lines improvement and 14 of 36 eyes had worsening of vision, of which 13 eyes had a decrease of 1-2 lines and 1 eye had a 3-line decrease. For the 27 eyes that continued aflibercept treatment for 6 months, 8 of 27 eyes had improvement of vision: 6 eyes had improvement of 1-2 lines and 2 eyes improved 3 lines. There were 10 of 27 eyes that had worsening of vision after 6 months; all eyes had a change of 1-2 lines (Table 3). Taken together, our data showed complete resolution of intraretinal and subretinal fluid on OCT in 6 of 36 eyes after an average of 1.5 (range 1-3) intravitreal injections. There was a reduction of intraretinal and/or subretinal fluid on OCT in 18 of 36 eyes at the visit after the third injection; and for all 14 of the 18 improved eyes that continued
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
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TABLE 1. Summary of Clinical Characteristics and Central Macular Thickness for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
Age/Sex
Eye
74/F 72/F 85/M 87/F 87/F 87/F 76/F 80/M 79/F 79/F 82/F 85/M 62/M 76/M 68/F 80/M 85/F 86/F 88/F 78/F 75/M 83/M 60/M 60/M 67/M 77/M 77/M 74/F 69/M 84/F 77/F 77/F 75/F 85/F 88/F 79/M
OS OD OD OD OD OS OD OS OD OS OS OS OD OD OD OD OD OS OD OD OD OD OD OS OD OD OS OS OD OS OD OS OS OD OS OD
Total BZB or RZB Prior to AFL
BZB
RZB
CMT (mm) at Switch to AFL
CMT (mm) After AFL 33
CMT Change (mm) at 3 Months
CMT (mm) After 6 Months.
CMT Change (mm) at 6 Months
22 28 24 24 6 6 10 41 20 38 21 41 9 21 19 74 21 44 31 14 10 45 31 31 9 34 31 31 9 20 24 21 29 26 15 42 25.6
21 19 12 11 4 4 0 21 20 31 19 23 8 16 7 74 5 44 3 4 3 18 13 13 4 1 1 25 8 10 17 9 13 11 15 36 15.0
1 9 12 13 2 2 10 20 0 7 2 18 1 5 12 0 16 0 28 10 7 27 18 18 5 33 30 6 1 10 7 12 16 15 0 6 10.6
340 385 532 261 181 329 1027 350 323 505 386 595 398 751 296 451 430 397 260 418 535 514 388 174 254 398 354 341 471 277 680 387 398 317 312 357 410
233 293 316 237 182 274 784 271 247 369 323 486 203 757 277 385 339 374 248 272 608 408 235 155 246 398 359 190 386 328 586 360 423 314 266 309 346
107 92 216 24 1 55 243 79 76 136 63 109 195 6 19 66 91 23 12 146 73 106 153 19 8 0 5 151 85 51 94 27 25 3 46 48 64.8 2.9 3 10-6
232 183 296
108 202 236
168 198
13 131
284
66
351
35
198 517 271 313 373 374 222 282 528 403 215 151 255 369 361 189 250 266
200 234 25 138 57 23 38 136 7 111 173 23 1 29 7 152 221 11
392 330
6 13
295
87.2 5.2 3 10-6
AFL ¼ aflibercept; BZB ¼ bevacizumab; CMT ¼ central macular thickness; RZB ¼ ranibizumab. a P value was calculated using Student t test.
aflibercept for at least 6 months, a continued beneficial effect was achieved. The OCT appearance was unchanged in 15 of 36 eyes at the visit after the third injection, which had a continued stability in 9 eyes at 6 months and improvement in 1 eye compared with the visit at the first aflibercept injection. In total, 9 eyes had a change in treatment between the visit after the third injection and the 6-month visit, for reasons mentioned previously. In 3 of 36 eyes, there was a total increase in the CMT at the 3-month visit compared with the first aflibercept injection. 4
However, with continued aflibercept injections the fluid had decreased and the CMT had returned to the same or a decreased level at the 6-month visit, compared with the initial visit. Representative OCT images from 3 eyes with a clinical impression of improvement, stable appearance, and worsening after 3 monthly aflibercept injections are seen in the Figure. For the 5 patients with both eyes included in the study, 3 individuals had improvement in 1 eye, whereas the other eye was stable; and 2 patients had a stable appearance in both eyes.
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TABLE 2. Thickness of Central Retina and Pigment Epithelial Detachment (in Micrometers) for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
CRT at Switch
CRT After 33 AFL
Change After 33 AFL
CRT After 6 Months
Change After 6 Months
340 328 303 261 181 329 288 317 223 187 235 435 308 625 296 195 302 218 211 315 258 239 337 143 254 374 291 311 471 277 302 270 372 208 312 319 295
233 258 216 237 182 274 279 230 158 166 167 342 170 638 277 166 199 207 229 194 280 194 224 135 246 378 293 153 386 328 269 230 384 159 266 257 250
107 70 87 24 1 55 9 87 65 21 68 93 138 13 19 29 103 11 18 121 22 45 113 8 8 4 2 158 85 51 33 40 12 49 46 62 45.3 2.0 3 10-6
232 142 213
108 186 90
168 198
13 131
224
93
196
39
173 309 271 146 232 213 210 192 261 200 205 138 255 341 256 158 250 266
135 316 25 49 70 5 1 123 3 39 132 5 1 33 35 153 221 11
348 152
220 1.14 3 10-5
PED at Switch
PED After 33 AFL
Change After 33 AFL
57 229
35 100
22 129
739 33 100 318 151 160 90 126
505 41 89 203 156 144 33 119
234 8 11 115 5 16 57 7
256 128 179 49 103 277 275 51 31
219 140 167 19 78 328 214 11 20
24 63 30
PED After 6 Months
Change After 6 Months
41 83
16 146
60
27
155
4
25 208
65 82
37 12 12 30 25 51 61 40 11
167 141 161 12 90 267 203 10 13
89 13 18 37 13 10 72 41 18
20 66 37
4 3 7
28 105 31
4 42 1
24 56
378 117 26 109
317 130 39 155
61 13 13 46
44 178
18 69
77.4
38 153
52 127
14 25.9 .015
101.1
13.3 .14
AFL ¼ aflibercept; CRT ¼ central retinal thickness; PED ¼ pigment epithelial detachment. P value was calculated using Student t test.
a
DISCUSSION IN THIS RETROSPECTIVE OBSERVATIONAL CASE SERIES,
a response was studied in eyes that developed resistance to repeated treatments with either bevacizumab or ranibizumab and were subsequently switched to at least 3 monthly injections of aflibercept. In 32 of the 36, the treatment had already been switched from bevacizumab or ranibizumab to the other medication prior to the switch to aflibercept, indicating that a significant portion of the eyes observed VOL. -, NO. -
in the study had exhibited nonresponsiveness to 2 anti-VEGF agents. There was a significant average decrease in the CMT at the visit after the third aflibercept injection and after 6 months. The change was significant both for the standard Spectralis algorithm and with manual measurement of the OCT image, suggesting that the standard algorithm used in clinical practice identified a trend similar to the more accurate manual measurement technique. When the subfoveal CRT and the PED thickness were measured, a significant average decrease was observed for both CRT
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
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TABLE 3. Visual Acuity (in logMAR) for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
VA at First Anti-VEGF
VA at Switch to AFL
VA After AFL 33
0.2 0.5 0.5 0.3 0.2 0.4 0.5 0.2 0.55 0.1 0.2 0.5 0.1 0.55 0.3 0.4 0.4 0.5 0.5 0.2 0.2 0.4 0.2 0.4 0.55 0.2 0.2 0.7 0.1 0.55 0.3 0.1 0.3 0.7 0.3 0.5 0.36
0.1 0.8 0.9 0.2 0.5 2 0.3 0.5 0.1 0.6 0.7 0.6 1 0.4 0.3 0.2 0.5 0.3 0.5 0.8 0.2 0.4 0.5 0.3 0.5 0 0.1 0.6 0.1 0.55 0.3 0 0.1 0.8 0.9 0.4 0.45
0.2 1 0.9 0.1 0.4 2 0.4 0.5 0.5 0.5 0.7 0.8 1.3 0.6 0.3 0.2 0.5 0.3 0.55 0.7 0.2 0.3 0.3 0.5 0.5 0.1 0 0.6 0.1 0.7 0.4 0.3 0.1 0.8 0.8 0.5 0.45 .052
VA After 6 Months
0.2 1 0.9 0.3 2 0.5
0.8 1.3 0.4 0.2 0.3 0.2 0.4 0.4 0.7 0.1 0.4 0.2 0.4 0.5 0 0 0.7 0.1 0.4
0.2 0.8
0.43 .36
AFL ¼ aflibercept; VA ¼ visual acuity; VEGF ¼ vascular endothelial growth factor. a P value was calculated using Student t test.
and PED after 3 aflibercept injections, but only for the CRT at 6 months. This indicates that the initial response in PED thickness observed after 3 injections stabilized at 6 months. According to the manufacturer’s recommendation, the interval can be extended to 8 weeks after 3 initial monthly injections. However, some eyes were very sensitive to extension and developed an increased amount of subretinal fluid that subsequently decreased after shortening of the treatment interval. 6
In half of the study eyes, an improvement was observed in the amount of the subretinal or intraretinal fluid after 3 injections. This response supports the hypothesis that tachyphylaxis plays a role in at least some patients who have shown unresponsiveness to other anti-VEGF injections. The overall limited response in the other half of patients, however, appears to indicate that other factors are important. It is interesting to speculate that perhaps the neovascularization has become mature and enveloped with pericytes, making it less responsive to any antiVEGF agent. Treatment with an anti-VEGF agent combined with therapy targeting pericytes by blocking a platelet-derived growth factor receptor can disrupt more mature vascular complexes.18 The various mechanisms of nonresponse will require further study. Although there was a significant decrease in CMT, the visual acuity did not change significantly. The discrepancy between anatomic improvement and functional outcome could be attributable to development of subretinal scarring and loss of foveal photoreceptors at an earlier stage of the disease. This study was a retrospective, noncontrolled chart review with the purpose of observing the outcome after a switch to aflibercept treatment in patients with 1 or 2 eyes with exudative AMD, resistant to treatment with bevacizumab, ranibizumab, or both in a clinic setting. The studied eyes had active exudative AMD with intraretinal and/or subretinal fluid treated with multiple monthly anti-VEGF injections and were switched to aflibercept shortly after this medication became available for treatment at the Vitreoretinal Clinic at the University of Iowa. This study was not intended to observe the longterm effect of aflibercept treatment or the long-term effect of bevacizumab or ranibizumab prior to switching to aflibercept. The change in retinal fluid volume, the change in the nonfoveal CMT, and the change in CMT more frequently than at monthly intervals were not studied. The test-retest variability was not evaluated, limiting the data interpretation to the group level with a limited assessment of CMT or visual acuity change on an individual level. In 6 patients, both eyes were included in the study, since we found it valuable for clinical practice, although this may be biased for patient-specific outcomes. The aflibercept treatment was stopped in 2 eyes because of an increase of subretinal fluid in both eyes and worsening of vision in 1 eye, indicating that aflibercept is not optimal for some eyes that develop unresponsiveness to other anti-VEGF injections. One eye had bacterial endophthalmitis during the observed treatment period with aflibercept; after standard surgical and antibiotic treatment, the visual acuity returned to the same level as at the visit of the first aflibercept treatment. In conclusion, aflibercept resulted in a significant average decrease in CMT after both 3 and 6 months. There was no significant average change in visual acuity. The eyes studied had received several injections of
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FIGURE. Treatment response in exudative age-related macular degeneration after switching to aflibercept from bevacizumab or ranibizumab. Ocular coherence tomography (OCT) horizontal sections from 3 eyes from different patients exhibit the evolution of subretinal or intraretinal fluid and central macular thickness. (Top row) Persistent subretinal fluid at the visit of the first aflibercept injection. (Second row) Images corresponding to the OCT scan 1 month after the first injection. (Third row) Retina examination at the visit after the second injection. (Bottom row) Retina examination after the third injection. There is improvement for eye #28 (left column), stable appearance for eye #25 (central column), and worsening for eye #30 (right column). The central macular thickness (mm) is indicated for each panel.
bevacizumab, ranibizumab, or both prior to the aflibercept regimen. Treatment with aflibercept can be considered on an individual basis as an alternative treatment in eyes with
active exudative AMD that do not respond to other antiVEGF treatments, and the response should be monitored closely.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. The authors are supported by NIH, Bethesda, Maryland, Grant K08EY020530 and the BrightFocus Foundation, Clarksburg, Maryland (V.B.M.), Research to Prevent Blindness, Inc, New York, NY (V.B.M., J.C.F.), and a career development award grant by Foundation Fighting Blindness, Columbia, Maryland (B.B.). Contributions of authors: design and conduct of the study, data collection, and management (B.B., J.C.F., V.B.M.); analysis and interpretation of the data and preparation, review, and approval of the manuscript (B.B., E.H.S., H.C.B., E.M.S., S.R.R., J.C.F., V.B.M.).
REFERENCES 1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1432–1444. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419–1431. 3. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119(7):1388–1398. 4. Folk JC, Stone EM. Ranibizumab therapy for neovascular age-related macular degeneration. N Engl J Med 2010; 363(17):1648–1655. 5. Keane PA, Liakopoulos S, Ongchin SC, et al. Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related
VOL. -, NO. -
6.
7.
8. 9.
10.
11.
macular degeneration. Invest Ophthalmol Vis Sci 2008; 49(7):3115–3120. Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29(6):723–731. Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115(12):2199–2205. Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol 2012;96(1):1–2. Gasperini JL, Fawzi AA, Khondkaryan A, et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 2012;96(1):14–20. Brown SM, Khanani AM, McCartney DL. The effect of daily use of brimonidine tartrate on the dark-adapted pupil diameter. Am J Ophthalmol 2004;138(1):149–151. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals:
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12.
13. 14.
15.
8
assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford) 2007;46(12):1828–1834. 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(17):11393–11398. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92(5):667–668. Stewart MW. Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol 2012;6:1175–1186. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119(12):2537–2548.
16. Roller AB, Folk JC, Patel NM, et al. Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. Retina 2011;31(9): 1848–1855. 17. Smretschnig E, Krebs I, Moussa S, Ansari-Shahrezaei S, Binder S. Cirrus OCT versus Spectralis OCT: differences in segmentation in fibrovascular pigment epithelial detachment. Graefes Arch Clin Exp Ophthalmol 2010;248(12): 1693–1698. 18. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111(9):1287–1295.
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Biosketch Benjamin Bakall received his medical degree and PhD at Uppsala University, Uppsala, Sweden. He continued his research on Best vitelliform macular dystrophy during a postdoctoral fellowship at University of Arizona, Tucson, Arizona, where he also completed his ophthalmology residency. He is currently a medical retina/inherited retinal disease fellow at University of Iowa, sponsored by the Foundation Fighting Blindness Alan Laties career development award. Dr Bakall intends to pursue a career in medical retina and inherited retinal diseases.
VOL. -, NO. -
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
8.e1
PURPOSE:
To evaluate the outcome of intravitreal injection of aflibercept in cases with exudative agerelated macular degeneration, (AMD) resistant to injections of bevacizumab or ranibizumab. DESIGN: Retrospective observational case series. METHODS: A retrospective chart review at a single institution was conducted to identify patients with exudative AMD and choroidal neovascularization (CNV) in 1 or both eyes resistant to treatment with ranibizumab or bevacizumab who were switched to treatment with at least 3 monthly injections of aflibercept. In total, 36 eyes from 31 patients were included. The demographic data, visual acuities, central macular thickness on optical coherence tomography (OCT), complications, and number of injections were reviewed. RESULTS: The mean patient age was 79 years (range 60-88). There were 13 male and 18 female patients. The number of prior injections with either bevacizumab or ranibizumab ranged from 6-74. After 3 monthly injections of aflibercept, there was a reduction of either subretinal or intraretinal fluid in 18 of 36 (50.0%) of the treated eyes; the amount of fluid remained stable in 15 eyes (41.7%) and worsened in 3 eyes (8.3%). A significant average decrease was observed for the central macular thickness after 3 injections of 65 mm (P [ 2.9 3 10-6), with no significant change in visual acuity. CONCLUSIONS: Aflibercept therapy appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intraretinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab. (Am J Ophthalmol 2013;-:-–-. Ó 2013 by Elsevier Inc. All rights reserved.)
A
GE-RELATED MACULAR DEGENERATION (AMD) IS
the most common cause of irreversible blindness in the industrialized world. Two landmark clinical trials using intravitreal injections of the humanized monoclonal antibody fragment ranibizumab (Lucentis) in eyes
Accepted for publication Feb 24, 2013. From the Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals & Clinics (B.B., J.C.F., H.C.B., E.H.S., E.M.S., S.R.R., V.B.M.); and Omics Laboratory, The University of Iowa (V.B.M.), Iowa City, Iowa. Inquiries to Vinit B. Mahajan, Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.02.017
Ó
2013 BY
with new-onset neovascular AMD showed that over 90% of treated eyes lost fewer than 15 letters after 24 months of follow-up and the visual acuity could be improved in 33.3%-40%.1,2 This improvement was associated with the drug’s ability to reduce intraretinal edema, subretinal fluid, and hemorrhage. A recent randomized, multicenter, 2-year clinical trial sponsored by the National Institutes of Health revealed that bevacizumab, a humanized murine antibody to vascular endothelial growth factor (VEGF), was noninferior compared with ranibizumab for the treatment of exudative AMD.3 Bevacizumab and ranibizumab injections have had a significant impact on preserving vision and preventing blindness.4 Some patients, however, have a good initial response with resolution of fluid, but then later become resistant to further treatment and develop recurrent exudation with vision loss.5,6 The mechanism of this resistance to treatment with these drugs is not known, but one possibility is tolerance or tachyphylaxis, manifested by a decreased response over time to repeated treatment with a medication.7 Tachyphylaxis sometimes can be reversed by increasing the dose or halting therapy for a period of time before reinstating the same treatment.8 Tachyphylaxis has been suggested in patients treated for exudative AMD.7 Some eyes have shown better resolution of fluid after switching anti-VEGF treatment.9 Tachyphylaxis has been proposed for a number of other treatments, including brimonidine and infliximab.10,11 In a study performed at the National Eye Institute, Forooghian and associates observed 6 eyes that developed tachyphylaxis after repeated bevacizumab injections.6 Gasperini and associates reported a significant decrease of subretinal fluid in the majority of tachyphylactic patients after switching treatments from either ranibizumab or bevacizumab to the other medication. The study showed that 81% of the patients responded favorably after changing intravitreal injection medication.9 Aflibercept is a novel VEGF inhibitor, with a high affinity for VEGF. It is a protein constructed by fusion of the second binding domain of the receptor VEGFR1 and the third binding domain of the receptor VEGFR2 to the crystalline portion of IgG1.12 This has resulted in aflibercept’s having a significantly higher affinity in vitro to VEGF compared with both bevacizumab and ranibizumab13 The intravitreal half-life of aflibercept is 4.7 days in rabbit eyes, which is longer than ranibizumab (2.9 days) and
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
comparable with bevacizumab (4.3 days). The combined high affinity and longer half-life has led to a calculated duration of effect of a single intravitreal injection of 2 mg aflibercept of 48-83 days.13,14 Monthly treatment with aflibercept has been shown to improve the vision in exudative AMD in 2 clinical trials. The treatment with 3 initial monthly injections of 2 mg aflibercept, followed by injections every 8 weeks, has been shown to be noninferior compared with monthly treatments with either aflibercept or ranibizumab.15 Bevacizumab is a humanized murine antibody to VEGF and ranibizumab is a humanized antigen-binding fragment to VEGF, whereas aflibercept is a fusion protein receptor with much higher binding affinity to VEGF than both bevacizumab and ranibizumab. Therefore, an important question is whether eyes that have become resistant to anti-VEGF molecules respond to aflibercept injections. The purpose of this study is to help answer this question by reporting on an initial cohort of eyes that became resistant to treatment with bevacizumab or ranibizumab and then were switched to injections of aflibercept.
METHODS A RETROSPECTIVE OBSERVATIONAL CASE SERIES WAS
performed to study the outcome in eyes with exudative AMD, resistant to the treatment of monthly injections with bevacizumab or ranibizumab, that were switched to at least 3 monthly injections of aflibercept therapy. A written consent was obtained from the patients prior to each injection treatment. The Institutional Review Board for human subjects research at the University of Iowa approved the study protocol for human subjects. The study was compliant with HIPAA (the Health Insurance Portability and Accountability Act of 1996) and adhered to the tenets of the Declaration of Helsinki. Charts were reviewed for patients treated in the Vitreoretinal Clinic at the University of Iowa Department of Ophthalmology and Visual Sciences. Intravitreal injections were performed using the same procedure in all patients, as previously described.16 Inclusion criteria were age >60 years and a diagnosis of exudative AMD, including presence of drusen, as well as pigment epithelial changes in combination with choroidal neovascularization, confirmed by fluorescein angiogram and optical coherence tomography (OCT) at the initial clinic visit. The criteria also included only eyes that had been previously injected with either 1.25 mg bevacizumab or 0.5 mg ranibizumab (Avastin and Lucentis, respectively; Genentech Inc, San Francisco, California, USA) and had an initial response (decrease of retinal edema and subretinal fluid), followed by a recurrent increase or persistent subretinal fluid or retinal edema on OCT. The intraretinal or subretinal fluid had to be present for a minimum of 3 months prior to the first aflibercept 2
injection. This fluid had to be refractory to continued monthly intravitreal injections with the same drug or a change from either bevacizumab or ranibizumab to the other drug with 3 monthly injections administered the 3 months prior to the first aflibercept injection. The criteria for treatment with aflibercept were the same as retreatment criteria for bevacizumab or ranibizumab regarding presence of intraretinal or subretinal fluid. Finally, the last criterion was that at least 3 initial 2-mg aflibercept injections every 4-6 weeks had been administered, followed by a visit within 4-8 weeks after the third aflibercept injection. Patient charts were reviewed until 6 months after the first aflibercept injection. At each visit the visual acuity was measured using a standardized Snellen chart and a comprehensive eye examination, and OCT imaging was performed using Spectralis OCT (Heidelberg Engineering, Carlsbad, California, USA) or Cirrus HD-OCT (Carl Zeiss Meditech, Dublin, California, USA). With Spectralis, 20 3 15degree volume scans containing 19 sections separated by 240 mm were used. The scans were acquired in highspeed mode. The central macular thickness (CMT) was equivalent according to the distance between the 2 algorithm lines. The Spectralis algorithm for placement of the segmentation line in an OCT with a vascular pigment epithelial detachment (PED) has been demonstrated to exhibit a significant difference compared with manual measurement of the CMT.17 Therefore, the CMT, central retinal thickness (CRT), and PED were also measured using the caliper function for the section corresponding to the foveal depression. CMT was measured from the foveal depression to the Bruch membrane; alternatively, where the PED obscured the outer retinal structures, it was measured to the estimated location of the Bruch membrane. CRT was measured from the foveal depression to the inner part of the PED along the CMT measurement line. The PED was calculated as the difference between the CMT and the CRT. The same numerical scan for each individual was analyzed at the different time points. With Cirrus, the 512 3 128 scan pattern was performed consisting of 128 horizontal lines of 512 A-scans per line. The collected demographic data included patient age; sex; laterality of the treated eye; number of ranibizumab, bevacizumab, and aflibercept injections; the time between injections; and the response to treatment as determined by the OCT and visual acuity. The CMT on OCT measurements were collected from the visit of the first treatment visit with aflibercept and until 6 months after the first aflibercept injection. An assessment of the OCT appearance was performed for the images from the selected follow-up visits and compared with the OCT from the visit of the first aflibercept injection. A definite (qualitative visible) change in macular thickness or subretinal or intraretinal fluid was graded as improved, stable, or worsened, similarly as performed in a previously published study of the OCT response after switching anti-VEGF treatment.9 The visual acuity was collected from the first visit of any anti-VEGF
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injection, at the visit of the first aflibercept injection, at the visit after the third injection, and at the visit 6 months after the first aflibercept injection. The Snellen visual acuity was converted to logMAR units. Measurements for the eyes with a change in treatment regimen or eyes that were lostto follow-up after the third injection, but before the 6-month visit, were not included in data collection for the 6-month visit. The occurrence of any severe postoperative complications, including infection, inflammation, arteriothrombotic events, or death within the 6 months after the first aflibercept injection was recorded. The significance of the difference of group means was tested with Student t test (2-tailed, equal variance).
RESULTS A TOTAL OF 36 EYES FROM 31 PATIENTS MET THE INCLUSION
criteria. The mean patient age was 79 years (range 60-88). There were 13 men and 18 women. Of the 36 eyes, 22 were the right eye and 14 were the left eye. The study eyes had received an average of 25.6 injections (range 6-74) prior to treatment with aflibercept, with a mean of 15.5 bevacizumab and 12.8 ranibizumab treatments. Thirty-two eyes had at least 1 trial of switching between bevacizumab and ranibizumab during the period from the first anti-VEGF injection until the first aflibercept treatment, whereas 3 eyes received only bevacizumab and 1 eye received only ranibizumab (Table 1). During the 6 months just prior to the change of treatment, an average of 5.2 injections (range 4-6) had been administered to the study eye. All eyes had received a series of 3 aflibercept injections given 4-6 weeks apart and the interval thereafter was extended at the discretion of the treating retina specialist. All 36 eyes had data collected for the visit after the third aflibercept injection. There were 27 eyes that continued aflibercept injections until at least 6 months after the first injection. The aflibercept treatment was stopped in 9 eyes prior to 6 months after the first injection. Four eyes in 4 patients were switched because of patient co-pay cost after the fifth injection, including 1 eye that in addition had increased subretinal fluid and worsened vision; 1 eye in 1 patient was lost to follow-up since the patient switched providers after the fifth injection; 1 patient was hospitalized after the fifth injection because of renal failure and was unable to return to the clinic for continued injections in the studied eye; 1 eye was treated with photodynamic therapy after the fourth injection because of persistent subretinal fluid; 1 eye had a change in treatment after the fifth injection because of patient preference; and 1 eye developed endophthalmitis after the fifth injection with coagulase-negative Streptococcus. The infected eye underwent vitrectomy and antibiotic injections, with the vision subsequently returning to 20/40, same as prior to the onset of aflibercept injections. VOL. -, NO. -
The manually measured, average CMT for the OCT at the time of switching therapies was 410 mm (range 1741027, median 387). The average CMT at the visit after the third aflibercept injection was 346 mm (range 155784, median 315), and after 6 months the average CMT was 296 mm (range 151-528, median 282). Compared with the CMT at the initial visit, there was a significant decrease in CMT after 3 months of 65 mm (P ¼ 2.9 3 10-6) and after 6 months of 87 mm (P ¼ 5.2 3 10-6) (Table 1). This suggests that aflibercept therapy improved CMT in previously unresponsive eyes. Using the standard Spectralis algorithm, the mean CMT on OCT prior to the first injection of aflibercept was 358 mm (range 181-579, median 335). The average CMT at the first visit after the third injection was 309 mm (range 162-623, median 274) and after 6 months was 298 mm (range 168-561, median 224). Compared with the visit at the first aflibercept injection, there was a significant average decrease in CMT after 3 injections of 48 mm (P ¼ 1.6 3 10-4) and a decrease of 60 mm (P ¼ 9.1 3 10-6) after 6 injections. In 28 of the 36 eyes, a PED was observed at the visit of the first aflibercept injection. Manual measurement of the CRT and calculation of the PED were performed in the 28 eyes with a PED. At the visit for the first aflibercept injection, the average CRT was 295 mm, significantly decreasing by 45 mm, to 250 mm (P ¼ 2.0 3 10-6), at 3 months and decreasing by 77 mm, to 220 mm (P ¼ 1.1 3 10-5), at 6 months. The average PED was 153 mm at the switch, decreasing by 26 mm (P ¼ .015), to 127 mm, at 3 months and decreasing by 13 mm (P ¼ .14), to 101 mm, after 6 months (Table 2). This indicates that aflibercept therapy reduced PED thickness after 3 months, but there were great fluctuations for the eyes observed at 6 months. The mean logMAR Snellen visual acuity at the visit of the first injection with either bevacizumab or ranibizumab was 0.36, which decreased to 0.45 (P ¼ .07) at the visit of the first aflibercept injection. After 3 injections, the average vision was 0.52 (P ¼ .052) and after 6 months the vision was 0.50 (P ¼ .36), which was not significantly changed. After 3 injections, 8 of 36 eyes had 1-2 lines improvement and 14 of 36 eyes had worsening of vision, of which 13 eyes had a decrease of 1-2 lines and 1 eye had a 3-line decrease. For the 27 eyes that continued aflibercept treatment for 6 months, 8 of 27 eyes had improvement of vision: 6 eyes had improvement of 1-2 lines and 2 eyes improved 3 lines. There were 10 of 27 eyes that had worsening of vision after 6 months; all eyes had a change of 1-2 lines (Table 3). Taken together, our data showed complete resolution of intraretinal and subretinal fluid on OCT in 6 of 36 eyes after an average of 1.5 (range 1-3) intravitreal injections. There was a reduction of intraretinal and/or subretinal fluid on OCT in 18 of 36 eyes at the visit after the third injection; and for all 14 of the 18 improved eyes that continued
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
3
TABLE 1. Summary of Clinical Characteristics and Central Macular Thickness for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
Age/Sex
Eye
74/F 72/F 85/M 87/F 87/F 87/F 76/F 80/M 79/F 79/F 82/F 85/M 62/M 76/M 68/F 80/M 85/F 86/F 88/F 78/F 75/M 83/M 60/M 60/M 67/M 77/M 77/M 74/F 69/M 84/F 77/F 77/F 75/F 85/F 88/F 79/M
OS OD OD OD OD OS OD OS OD OS OS OS OD OD OD OD OD OS OD OD OD OD OD OS OD OD OS OS OD OS OD OS OS OD OS OD
Total BZB or RZB Prior to AFL
BZB
RZB
CMT (mm) at Switch to AFL
CMT (mm) After AFL 33
CMT Change (mm) at 3 Months
CMT (mm) After 6 Months.
CMT Change (mm) at 6 Months
22 28 24 24 6 6 10 41 20 38 21 41 9 21 19 74 21 44 31 14 10 45 31 31 9 34 31 31 9 20 24 21 29 26 15 42 25.6
21 19 12 11 4 4 0 21 20 31 19 23 8 16 7 74 5 44 3 4 3 18 13 13 4 1 1 25 8 10 17 9 13 11 15 36 15.0
1 9 12 13 2 2 10 20 0 7 2 18 1 5 12 0 16 0 28 10 7 27 18 18 5 33 30 6 1 10 7 12 16 15 0 6 10.6
340 385 532 261 181 329 1027 350 323 505 386 595 398 751 296 451 430 397 260 418 535 514 388 174 254 398 354 341 471 277 680 387 398 317 312 357 410
233 293 316 237 182 274 784 271 247 369 323 486 203 757 277 385 339 374 248 272 608 408 235 155 246 398 359 190 386 328 586 360 423 314 266 309 346
107 92 216 24 1 55 243 79 76 136 63 109 195 6 19 66 91 23 12 146 73 106 153 19 8 0 5 151 85 51 94 27 25 3 46 48 64.8 2.9 3 10-6
232 183 296
108 202 236
168 198
13 131
284
66
351
35
198 517 271 313 373 374 222 282 528 403 215 151 255 369 361 189 250 266
200 234 25 138 57 23 38 136 7 111 173 23 1 29 7 152 221 11
392 330
6 13
295
87.2 5.2 3 10-6
AFL ¼ aflibercept; BZB ¼ bevacizumab; CMT ¼ central macular thickness; RZB ¼ ranibizumab. a P value was calculated using Student t test.
aflibercept for at least 6 months, a continued beneficial effect was achieved. The OCT appearance was unchanged in 15 of 36 eyes at the visit after the third injection, which had a continued stability in 9 eyes at 6 months and improvement in 1 eye compared with the visit at the first aflibercept injection. In total, 9 eyes had a change in treatment between the visit after the third injection and the 6-month visit, for reasons mentioned previously. In 3 of 36 eyes, there was a total increase in the CMT at the 3-month visit compared with the first aflibercept injection. 4
However, with continued aflibercept injections the fluid had decreased and the CMT had returned to the same or a decreased level at the 6-month visit, compared with the initial visit. Representative OCT images from 3 eyes with a clinical impression of improvement, stable appearance, and worsening after 3 monthly aflibercept injections are seen in the Figure. For the 5 patients with both eyes included in the study, 3 individuals had improvement in 1 eye, whereas the other eye was stable; and 2 patients had a stable appearance in both eyes.
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TABLE 2. Thickness of Central Retina and Pigment Epithelial Detachment (in Micrometers) for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
CRT at Switch
CRT After 33 AFL
Change After 33 AFL
CRT After 6 Months
Change After 6 Months
340 328 303 261 181 329 288 317 223 187 235 435 308 625 296 195 302 218 211 315 258 239 337 143 254 374 291 311 471 277 302 270 372 208 312 319 295
233 258 216 237 182 274 279 230 158 166 167 342 170 638 277 166 199 207 229 194 280 194 224 135 246 378 293 153 386 328 269 230 384 159 266 257 250
107 70 87 24 1 55 9 87 65 21 68 93 138 13 19 29 103 11 18 121 22 45 113 8 8 4 2 158 85 51 33 40 12 49 46 62 45.3 2.0 3 10-6
232 142 213
108 186 90
168 198
13 131
224
93
196
39
173 309 271 146 232 213 210 192 261 200 205 138 255 341 256 158 250 266
135 316 25 49 70 5 1 123 3 39 132 5 1 33 35 153 221 11
348 152
220 1.14 3 10-5
PED at Switch
PED After 33 AFL
Change After 33 AFL
57 229
35 100
22 129
739 33 100 318 151 160 90 126
505 41 89 203 156 144 33 119
234 8 11 115 5 16 57 7
256 128 179 49 103 277 275 51 31
219 140 167 19 78 328 214 11 20
24 63 30
PED After 6 Months
Change After 6 Months
41 83
16 146
60
27
155
4
25 208
65 82
37 12 12 30 25 51 61 40 11
167 141 161 12 90 267 203 10 13
89 13 18 37 13 10 72 41 18
20 66 37
4 3 7
28 105 31
4 42 1
24 56
378 117 26 109
317 130 39 155
61 13 13 46
44 178
18 69
77.4
38 153
52 127
14 25.9 .015
101.1
13.3 .14
AFL ¼ aflibercept; CRT ¼ central retinal thickness; PED ¼ pigment epithelial detachment. P value was calculated using Student t test.
a
DISCUSSION IN THIS RETROSPECTIVE OBSERVATIONAL CASE SERIES,
a response was studied in eyes that developed resistance to repeated treatments with either bevacizumab or ranibizumab and were subsequently switched to at least 3 monthly injections of aflibercept. In 32 of the 36, the treatment had already been switched from bevacizumab or ranibizumab to the other medication prior to the switch to aflibercept, indicating that a significant portion of the eyes observed VOL. -, NO. -
in the study had exhibited nonresponsiveness to 2 anti-VEGF agents. There was a significant average decrease in the CMT at the visit after the third aflibercept injection and after 6 months. The change was significant both for the standard Spectralis algorithm and with manual measurement of the OCT image, suggesting that the standard algorithm used in clinical practice identified a trend similar to the more accurate manual measurement technique. When the subfoveal CRT and the PED thickness were measured, a significant average decrease was observed for both CRT
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
5
TABLE 3. Visual Acuity (in logMAR) for 36 Eyes With Resistance to Bevacizumab and/or Ranibizumab Prior to Switching to Aflibercept Treatment of Exudative Age-related Macular Degeneration
Eye No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Mean P valuea
VA at First Anti-VEGF
VA at Switch to AFL
VA After AFL 33
0.2 0.5 0.5 0.3 0.2 0.4 0.5 0.2 0.55 0.1 0.2 0.5 0.1 0.55 0.3 0.4 0.4 0.5 0.5 0.2 0.2 0.4 0.2 0.4 0.55 0.2 0.2 0.7 0.1 0.55 0.3 0.1 0.3 0.7 0.3 0.5 0.36
0.1 0.8 0.9 0.2 0.5 2 0.3 0.5 0.1 0.6 0.7 0.6 1 0.4 0.3 0.2 0.5 0.3 0.5 0.8 0.2 0.4 0.5 0.3 0.5 0 0.1 0.6 0.1 0.55 0.3 0 0.1 0.8 0.9 0.4 0.45
0.2 1 0.9 0.1 0.4 2 0.4 0.5 0.5 0.5 0.7 0.8 1.3 0.6 0.3 0.2 0.5 0.3 0.55 0.7 0.2 0.3 0.3 0.5 0.5 0.1 0 0.6 0.1 0.7 0.4 0.3 0.1 0.8 0.8 0.5 0.45 .052
VA After 6 Months
0.2 1 0.9 0.3 2 0.5
0.8 1.3 0.4 0.2 0.3 0.2 0.4 0.4 0.7 0.1 0.4 0.2 0.4 0.5 0 0 0.7 0.1 0.4
0.2 0.8
0.43 .36
AFL ¼ aflibercept; VA ¼ visual acuity; VEGF ¼ vascular endothelial growth factor. a P value was calculated using Student t test.
and PED after 3 aflibercept injections, but only for the CRT at 6 months. This indicates that the initial response in PED thickness observed after 3 injections stabilized at 6 months. According to the manufacturer’s recommendation, the interval can be extended to 8 weeks after 3 initial monthly injections. However, some eyes were very sensitive to extension and developed an increased amount of subretinal fluid that subsequently decreased after shortening of the treatment interval. 6
In half of the study eyes, an improvement was observed in the amount of the subretinal or intraretinal fluid after 3 injections. This response supports the hypothesis that tachyphylaxis plays a role in at least some patients who have shown unresponsiveness to other anti-VEGF injections. The overall limited response in the other half of patients, however, appears to indicate that other factors are important. It is interesting to speculate that perhaps the neovascularization has become mature and enveloped with pericytes, making it less responsive to any antiVEGF agent. Treatment with an anti-VEGF agent combined with therapy targeting pericytes by blocking a platelet-derived growth factor receptor can disrupt more mature vascular complexes.18 The various mechanisms of nonresponse will require further study. Although there was a significant decrease in CMT, the visual acuity did not change significantly. The discrepancy between anatomic improvement and functional outcome could be attributable to development of subretinal scarring and loss of foveal photoreceptors at an earlier stage of the disease. This study was a retrospective, noncontrolled chart review with the purpose of observing the outcome after a switch to aflibercept treatment in patients with 1 or 2 eyes with exudative AMD, resistant to treatment with bevacizumab, ranibizumab, or both in a clinic setting. The studied eyes had active exudative AMD with intraretinal and/or subretinal fluid treated with multiple monthly anti-VEGF injections and were switched to aflibercept shortly after this medication became available for treatment at the Vitreoretinal Clinic at the University of Iowa. This study was not intended to observe the longterm effect of aflibercept treatment or the long-term effect of bevacizumab or ranibizumab prior to switching to aflibercept. The change in retinal fluid volume, the change in the nonfoveal CMT, and the change in CMT more frequently than at monthly intervals were not studied. The test-retest variability was not evaluated, limiting the data interpretation to the group level with a limited assessment of CMT or visual acuity change on an individual level. In 6 patients, both eyes were included in the study, since we found it valuable for clinical practice, although this may be biased for patient-specific outcomes. The aflibercept treatment was stopped in 2 eyes because of an increase of subretinal fluid in both eyes and worsening of vision in 1 eye, indicating that aflibercept is not optimal for some eyes that develop unresponsiveness to other anti-VEGF injections. One eye had bacterial endophthalmitis during the observed treatment period with aflibercept; after standard surgical and antibiotic treatment, the visual acuity returned to the same level as at the visit of the first aflibercept treatment. In conclusion, aflibercept resulted in a significant average decrease in CMT after both 3 and 6 months. There was no significant average change in visual acuity. The eyes studied had received several injections of
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FIGURE. Treatment response in exudative age-related macular degeneration after switching to aflibercept from bevacizumab or ranibizumab. Ocular coherence tomography (OCT) horizontal sections from 3 eyes from different patients exhibit the evolution of subretinal or intraretinal fluid and central macular thickness. (Top row) Persistent subretinal fluid at the visit of the first aflibercept injection. (Second row) Images corresponding to the OCT scan 1 month after the first injection. (Third row) Retina examination at the visit after the second injection. (Bottom row) Retina examination after the third injection. There is improvement for eye #28 (left column), stable appearance for eye #25 (central column), and worsening for eye #30 (right column). The central macular thickness (mm) is indicated for each panel.
bevacizumab, ranibizumab, or both prior to the aflibercept regimen. Treatment with aflibercept can be considered on an individual basis as an alternative treatment in eyes with
active exudative AMD that do not respond to other antiVEGF treatments, and the response should be monitored closely.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. The authors are supported by NIH, Bethesda, Maryland, Grant K08EY020530 and the BrightFocus Foundation, Clarksburg, Maryland (V.B.M.), Research to Prevent Blindness, Inc, New York, NY (V.B.M., J.C.F.), and a career development award grant by Foundation Fighting Blindness, Columbia, Maryland (B.B.). Contributions of authors: design and conduct of the study, data collection, and management (B.B., J.C.F., V.B.M.); analysis and interpretation of the data and preparation, review, and approval of the manuscript (B.B., E.H.S., H.C.B., E.M.S., S.R.R., J.C.F., V.B.M.).
REFERENCES 1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1432–1444. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419–1431. 3. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119(7):1388–1398. 4. Folk JC, Stone EM. Ranibizumab therapy for neovascular age-related macular degeneration. N Engl J Med 2010; 363(17):1648–1655. 5. Keane PA, Liakopoulos S, Ongchin SC, et al. Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related
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6.
7.
8. 9.
10.
11.
macular degeneration. Invest Ophthalmol Vis Sci 2008; 49(7):3115–3120. Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29(6):723–731. Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115(12):2199–2205. Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol 2012;96(1):1–2. Gasperini JL, Fawzi AA, Khondkaryan A, et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 2012;96(1):14–20. Brown SM, Khanani AM, McCartney DL. The effect of daily use of brimonidine tartrate on the dark-adapted pupil diameter. Am J Ophthalmol 2004;138(1):149–151. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals:
AFLIBERCEPT AS TREATMENT IN AGE-RELATED MACULAR DEGENERATION
7
12.
13. 14.
15.
8
assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford) 2007;46(12):1828–1834. 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(17):11393–11398. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92(5):667–668. Stewart MW. Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol 2012;6:1175–1186. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119(12):2537–2548.
16. Roller AB, Folk JC, Patel NM, et al. Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. Retina 2011;31(9): 1848–1855. 17. Smretschnig E, Krebs I, Moussa S, Ansari-Shahrezaei S, Binder S. Cirrus OCT versus Spectralis OCT: differences in segmentation in fibrovascular pigment epithelial detachment. Graefes Arch Clin Exp Ophthalmol 2010;248(12): 1693–1698. 18. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111(9):1287–1295.
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Biosketch Benjamin Bakall received his medical degree and PhD at Uppsala University, Uppsala, Sweden. He continued his research on Best vitelliform macular dystrophy during a postdoctoral fellowship at University of Arizona, Tucson, Arizona, where he also completed his ophthalmology residency. He is currently a medical retina/inherited retinal disease fellow at University of Iowa, sponsored by the Foundation Fighting Blindness Alan Laties career development award. Dr Bakall intends to pursue a career in medical retina and inherited retinal diseases.
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