CONVERSION TO AFLIBERCEPT THERAPY VERSUS CONTINUING WITH RANIBIZUMAB THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION DEPENDENT ON MONTHLY RANIBIZUMAB TREATMENT IRMELA MANTEL, MD,*† CHRISTINA GIANNIOU, MD,*† ALI DIRANI, MD*† Purpose: To compare the effects of converting to aflibercept therapy with continuing ranibizumab therapy in eyes with neovascular age-related macular degeneration requiring monthly ranibizumab treatment. Methods: Patients were selected from the 104 patients (115 eyes) already enrolled in an “Observe and Plan” prospective case series that included treating neovascular age-related macular degeneration with ranibizumab for 24 months. Patients who still needed monthly retreatment at the end of a 2-year study were randomized to either continue ranibizumab therapy or to convert to aflibercept therapy. Outcome measures included average interval between treatments, resolution of exudative signs, number of retreatments, and change in visual acuity over 12 months (the third treatment year). Results: Nineteen patients (21 eyes) met the inclusion criteria. Ten eyes were randomized to receive aflibercept, and 11 eyes remained on ranibizumab. Groups were balanced for baseline characteristics. Outcomes were similar in the 2 groups over a 12month study duration, with no statistical difference. Conclusion: This comparative pilot study suggests that neovascular age-related macular degeneration requiring monthly retreatment with ranibizumab may respond in similar ways to both ranibizumab and aflibercept treatment. Larger sample sizes would be needed to confirm this observation. RETINA 36:53–58, 2016
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everal, Phase 3 multicenter pivotal trials have established intravitreal anti-vascular endothelial growth factor (VEGF) therapy as the gold standard treatment for neovascular age-related macular degeneration (nAMD). The anti-VEGF agent ranibizumab was introduced first1–3 followed by aflibercept several years later.4,5 Both agents potently inhibit VEGF and
have been shown to have equivalent efficacies, as determined by visual and structural outcomes.5 In most patients, injections can be administered less frequently than once a month using retreatment regimens, including the pro re nata approach,6 the treat-and-extend regimen,7 the “Observe and Plan” regimen,8 increased dosing,9 and fixed bimonthly retreatment.5 However, some patients still require monthly retreatment based on exudative signs at monthly examinations.10 Although these eyes may have a reasonable functional prognosis,11,12 clinicians tend to aim for a dry macula. To date, refractory or recurrent nAMD has been most often identified in patients treated with ranibizumab, because this drug has been used the longest in clinical practice. Several longitudinal studies in
From the *Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland; and †Medical Retina Clinic, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Irmela Mantel, MD, Fondation Asile des Aveugles, University Eye Hospital Jules-Gonin, Avenue de France 15, Case Postale 133, CH 1000 Lausanne 7, Switzerland; e-mail: [email protected]
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patients with refractory or recurrent nAMD have found that converting from ranibizumab or bevacizumab to aflibercept therapy seemed to have a beneficial effect on retinal structure13–18 and the number of required retreatments.17 However, the absence of a control group in these studies prohibits firm conclusions. It has been shown that disease activity (the amount of fluid) and retreatment needs may decrease over time,19,20 which may confound study results. Additional problems may include retrospective study designs, behavioral influences, and the possibility of regression to the mean.21 Prospective comparative trials, with well-defined treatment conditions, clear inclusion criteria, and balanced groups, would be required to understand whether a change of treatment improves the outcome. The aim of this study was to estimate the effect of converting to aflibercept therapy in a group of patients with nAMD who required monthly ranibizumab treatment, as compared with a balanced comparison group who continued with ranibizumab therapy. Methods We selected groups that were balanced for preceding treatment regimen, duration of anti-VEGF treatment, regimen, retreatment need, and demographics. To accomplish this, we performed an extension of a prospective clinical trial (protocol number 351/11, ethics committee VD) that was conducted over 2 years by the medical Retina Department of a single tertiary referral center (University Eye Hospital Jules-Gonin, Lausanne, Switzerland). The purpose of the prospective clinical trial was to evaluate the clinical value of an Observe and Plan treatment regimen for nAMD using intravitreal ranibizumab.8,20 This study was approved by the local ethics committee, and all study conduct adhered to the tenets of the Declaration of Helsinki. Applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research. All patients provided written informed consent for study participation. Patient Selection Patients were selected from a previously described nAMD study population. All patients had undergone the same prospective Observe and Plan retreatment regimen with ranibizumab.8 This previous prospective study included 115 eyes of 104 patients with treatmentnaive nAMD and active subfoveal choroidal neovascularization. All patients had a best-corrected visual acuity (BCVA) between 20/25 and 20/400, a maximum lesion
size of 12 disk areas, and had provided informed consent. The Observe and Plan retreatment regimen was fully described previously8 and is summarized below. After completion of a 24-month study period, patients who still needed monthly retreatment with ranibizumab based on optical coherence tomography (OCT) criteria (the presence of intraretinal or subretinal fluid) were eligible for the extension study. The need for monthly retreatment was based on the presence of refractory fluid when treatment was performed monthly or the recurrent fluid when the treatment interval was extended to 1.5 months. Of 25 eligible eyes, 21 eyes of 19 patients were randomized to either change to aflibercept treatment (Group A) or to remain on ranibizumab therapy (Group R). After converting to aflibercept or continuing on ranibizumab, the retreatment regimen remained the same, starting with 3 monthly injections and then extending the treatment intervals according to OCT criteria under an ongoing Observe and Plan regimen for 12 months. Clinical Investigations At each study visit, the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA and intraocular pressure were measured. Slit-lamp examination, dilated fundus examination, and spectral domain OCT were performed. The original 24-month study spectral domain OCT scans were obtained using the macular cube scan protocol (512 · 126 scan) of the Cirrus OCT (Carl Zeiss Meditec, Inc, Oberkochen, Germany). However, spectral domain OCT scans in the extension study were predominantly obtained with the 6 · 6-mm cube scan protocol (49 line scans) on the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography and indocyanine green angiography (Topcon TRC-50IX, Tokyo, Japan) were performed before initiating treatment. Fluorescein angiography was repeated approximately every year. “Observe and Plan” Treatment Regimen The Observe and Plan regimen is an interval-based variable dosing regimen. The methodology of the Observe and Plan treatment regimen has been fully described elsewhere.8 The concept of this regimen is to first measure and then to plan the ideal retreatment interval in a fixed but individualized retreatment regimen. After initiation of treatment with 3 monthly loading doses of intravitreal ranibizumab, each patient’s treatment-recurrence interval was determined during an observation phase. The resulting interval was then shortened by 2 weeks for the series of subsequently
SWITCH OR NOT IN REFRACTORY AMD MANTEL ET AL
planned injections. After 3 planned injections, patients were again assessed to allow for adjustment of the treatment interval every 6 months at the latest (patients were assessed after 2 planned injections if the interval was longer than 2 months). If signs of exudation were detected on OCT images (intraretinal or subretinal fluid) or fundus examination (hemorrhage), future treatment intervals were shortened by 2 weeks. Otherwise, the treatment intervals were lengthened by 2 weeks. The shortest allowed interval was 1 month, and the longest was 3 months. Clinical Outcome Analysis The outcome measures included the mean retreatment interval over a 12-month study period (overall third year of study participation) and the proportion of eyes achieving a longer retreatment interval than in the preceding 6 months (individual mean). In addition, we analyzed the proportion of patients with a dry retina (as determined with qualitative OCT image criteria), the number of injections, and change of BCVA. Quantitative OCT parameters (e.g., retinal thickness) were not examined because of frequent changes in OCT instrumentation during the study period. Statistical Evaluation The statistical analysis is mainly descriptive because of the limited power of the small sample size. For data at the end point of the study (BCVA), the last available measures were carried forward because of visits that were not performed monthly. Baseline for Group A was the time of the conversion to aflibercept treatment (approximately the end of the original 24-month study, depending on the time of the visit). Baseline for Group R, who continued with ranibizumab treatment, was Month 24. Treatment intervals that carried over into another treatment period (e.g., Year 4) were taken into account, but only according to the proportion of time within the evaluation period. Except for descriptive statistics, explorative analyses were performed using the Yates corrected chisquare test for categorical data and the Mann–Whitney U test for continuous variables. Statistical significance was defined as P , 0.05. Results Study Population Twenty-one eyes of 19 patients were ultimately included in this extension study. This represented 20% of the 105 eyes that had completed the previous
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24-month trial. During the 1-year study period (the third year of treatment), 10 eyes (9 patients) were converted to intravitreal aflibercept (Group A) and 11 eyes (10 patients) received intravitreal ranibizumab (Group R). All patients agreed to continue on the Observe and Plan regimen as an extension of the initial 24-month ranibizumab trial. Characteristics of patients in the 2 study groups were well balanced at baseline (Table 1). There was no significant difference between groups in age, BCVA before anti-VEGF therapy, BCVA improvement during the first 24 months of treatment, AMD lesion characteristics (e.g., pigment epithelium detachment), number of injections, or previous duration of treatment. Additionally, there was no difference in the proportion of eyes with persistent fluid on OCT (Group A, 70%; Group R, 73%) or that required monthly retreatment because of exudative recurrence under longer treatment intervals (Group A, 30%; Group R, 27%). Treatment Outcomes A summary of the treatment outcomes is given in Table 2. The mean retreatment interval during 12 months of this study was 1.13 months (standard deviation [SD] 0.14 months) in Group A and 1.14 months (SD 0.18 months) in Group R. Approximately half of the eyes in each group had a longer retreatment interval during the study period than during 6 months before this extension study (treatment months, 18–24). The number of eyes that attained a dry macula during the 12-month study period was 4 of 10 eyes (40%) in Group A and 4 of 11 eyes (36%) in Group R. The mean number of injections was 10.7 (SD 1.2) and 10.7 (SD 1.5) in Groups A and R, respectively. Mean visual acuity decreased by 2.0 ETDRS letters (SD 3.0) in Group A and increased by 0.5 ETDRS letters (SD 2.5) in Group R, a difference that was nearly significant (P = 0.07). The preceding BCVA data was therefore compared in a post hoc analysis. The change in BCVA from anti-VEGF treatment initiation to baseline (treatment Months 0–24) was not different (see also baseline characteristics, Table 1), but the immediate response to the ranibizumab loading dose at the initiation of anti-VEGF therapy was significantly poorer in Group A (−1.3 letters, SD 12.0) than in Group R (+9.6 letters, SD 11.0) (P = 0.026). Discussion In this study, we explored the effect of converting patients with nAMD from ranibizumab to aflibercept therapy and compared these results to patients with nAMD continuing on ranibizumab therapy. All
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 1 Table 1. Patient Characteristics at Baseline
Age, years BCVA before anti-VEGF treatment, Snellen (ETDRS letters; SD) BCVA change between therapy initiation and baseline, ETDRS letters Previous treatment duration, months Total number of previous injections Number of injections during the 6 months before baseline Mean interval injections during the 6 months before baseline Persistent fluid on OCT, % Angiographic type of CNV Predominantly classic Minimally classic Occult RAP Presence of PED, %
All Studied Patients
Group A
Group R
N = 21 Eyes
N = 10 Eyes
N = 11 Eyes
76.0 (23.5) 20/50−1 (64.4; 14.9)
77.0 (25.0) 20/50 (65.2; 11.5)
75.2 (23.3) 20/50−1 (63.6; 17.9)
6.6 (15.1)
5.6 (15.8)
7.5 (15.1)
24.3 (2.6) 20.7 (2.9) 5.4 (0.6)
24.6 (3.9) 21.3 (2.6) 5.4 (0.7)
24.0 (0) 20.1 (3.2) 5.3 (0.5)
1.1 (0.1)
1.1 (0.2)
1.1 (0.1)
15 (71)
7 (70)
8 (73)
4 4 12 1 9 (43)
1 2 7 0 5 (50)
3 2 5 1 4 (36)
All patients had nAMD that required monthly ranibizumab retreatment after 2 years of ranibizumab therapy. Data are presented as mean (SD), where applicable. CNV, choroidal neovascular membrane; Group A, group aflibercept; Group R, group ranibizumab; PED, pigment epithelium detachment; RAP, retinal angiomatous proliferation.
included patients required monthly retreatment at baseline. In addition, all patients entered the study at the same time point of their overall treatment duration, which was 2 years after initiation of ranibizumab therapy, under the same interval-based regimen. The well-balanced groups showed very similar results in mean treatment interval, proportion of patients with longer intervals, proportion with dry maculae, mean number of injections, and BCVA. The small sample size does not allow for a statistical conclusion; therefore, this study should be considered an exploratory pilot study. The similarity of the results in the two groups may contradict the frequently reported benefit of converting to aflibercept in cases of refractory or recurrent nAMD.13–18
Our current understanding of the usefulness of changing from ranibizumab to aflibercept in refractory or recurrent cases relies on noncomparative switch studies, all but one15 of which have been retrospective.13–18 Although these studies are interesting and clearly suggest a benefit in converting to aflibercept, the absence of a well-balanced control group makes them difficult to interpret because of the potential effect of evolution over time, the possibility of regression to the mean, inhomogeneous times of treatment change, differences in reported outcomes, and uncertainty regarding the adequacy of the previous treatment.21 Thus, even a noticeable improvement found in a longitudinal noncomparative switch study might not provide reliable data with which to make conclusions about the
Table 2. Anatomical, Functional, and Treatment Results of the 1-Year Study, Corresponding With the Third Year of AntiVEGF Treatment for AMD That Required Monthly Ranibizumab Retreatment After 2 Years of Ranibizumab Therapy
Retreatment interval, months (SD) Eyes with increased treatment interval, % Eyes with dry macula at some time during the study (Y3), % Number of injections (SD) BCVA change from baseline, ETDRS letters (SD)
All Patients
Group A
Group R
N = 21 Eyes
N = 10 Eyes
N = 11 Eyes
1.1 (0.2) 11 (52) 8 (38)
1.1 (0.1) 6 (60) 4 (40)
1.1 (0.2) 5 (45) 4 (36)
10.7 (1.3) −0.7 (3.0)
10.7 (1.2) −2.0 (3.0)
10.7 (1.5) 0.5 (2.5)
The groups either continued on ranibizumab or converted to aflibercept. Baseline, the time of treatment change (Group A) or Month 24 of the total treatment duration (Group R); Group A, group aflibercept; Group R, group ranibizumab; Y3, Year 3 (the 12-month study duration, corresponding with the third year of each patient’s treatment period).
SWITCH OR NOT IN REFRACTORY AMD MANTEL ET AL
usefulness of medication change. The assumption of no change under continuation of the same medication could be incorrect; it would not correspond with the observation that retreatment needs generally decrease over time.19,20 Eyes with the greatest need for retreatment tend to have longer treatment intervals over time, even when continuing with the same drug (as shown in the 24-month results of the Observe and Plan study).20 In addition, Jang et al11 in their study of ranibizumab reported that refractory subretinal fluid may disappear at any time during ongoing monthly treatment with the same medication. Therefore, time is clearly a factor in the outcome. To properly assess the effect of a treatment change on outcome, a prospective comparative study with half of the patients remaining on the original treatment and half of them changing to a different one is required. However, several study conditions should be implemented. First, the previous treatment regimen should be standardized, maintaining uniform timelines for retreatment; longer intervals between injections increase the likelihood of fluid in the retina. In particular, the last treatment intervals before the medication change should be carefully planned, because they influence the amount of fluid present at the time of the change. The ideal situation would be the end of a prospective clinical trial. Second, the times of treatment follow-up should be uniform, because the behavior of nAMD can change over the years. Third, the type of retreatment regimen should be standardized. Fourth, the demographic and lesion characteristics of the study groups should be balanced. To the best of our knowledge, our study is the only one that has fulfilled these requirements. Unfortunately, our sample size is too small to show a statistically significant effect. However, as the only comparative data of well-balanced comparison groups available to date, it may serve as a pilot study, allowing for power calculations for future prospective comparative switch trials. Given the similarities in structural and treatment characteristics between our study groups, it is evident that the sample size of each group would need to be .100 to demonstrate a statistical difference. If the study were performed at the end of a previous prospective trial with the same recruitment proportion (20%) as in our study, the previous clinical trial would require more than 1,000 patients. The similar results in our two study groups were somewhat surprising to us. Not only did we expect to see some difference based on previous switch reports and because of a possible ranibizumab tachyphylaxis,22–24 but a switch benefit also seemed likely because of the higher binding affinity of aflibercept25 and its theoretically longer ligand-binding activity.26
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In addition, the placental growth factor antagonism of aflibercept could play a role in the treatment of nAMD. Placental growth factor has been identified in the choroidal neovascularization process,27 and it stimulates production of VEGF.28 However, the VIEW studies showed no differences in retreatment needs, change in central retinal thickness, or in visual outcomes for a general nAMD cohort.4 A recent study also found that converting from ranibizumab to aflibercept did not reduce the need for retreatment without previous selection of refractory cases.29 The Observe and Plan regimen used in this study is an interval-based regimen that seems to be useful in capturing changing retreatment needs over time. However, because of the relatively delayed reassessment visits (every 3–6 months), a 12-month observation period was needed to detect these changes. One parameter that tended to be different between the aflibercept and ranibizumab groups was the change in visual acuity over the 12-month study period (the third treatment year). Group A tended to have poorer visual outcomes than Group R. We assume that this difference resulted from the lower BCVA gain in Group A 3 months after treatment initiation; this has been shown to be a risk factor for later BCVA loss.30–33 A poor initial response to intravitreal anti-VEGF therapy may indicate more severe degenerative changes. Our study has some important limitations. The sample size is too small for reliable statistical comparison between the groups; therefore, our study may be considered a pilot comparative study. In addition, we could not obtain homogenous quantitative automated OCT measurements because of frequent changes of OCT machines during the study period. Finally, this study does not distinguish between phenotypical subgroups, which might show different sensitivities to the drugs. In conclusion, this comparative pilot study suggests that in patients with nAMD requiring monthly retreatment with ranibizumab, there may be little clinical difference between changing to aflibercept and remaining on ranibizumab treatment. Although the small numbers prohibit any statistical conclusions, the similar results in the groups may challenge reports of the benefit of changing treatment. Wellconstructed prospective studies with large and balanced groups would be needed to determine the benefit of switching from ranibizumab to aflibercept in patients with nAMD. Key words: anti-VEGF therapy, ranibizumab, aflibercept, neovascular age-related macular degeneration, observe and plan regimen.
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References 1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 2. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116:57–65. 3. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 4. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121:193–201. 5. Bressler NM, Chang TS, Varma R, et al. Driving ability reported by neovascular age-related macular degeneration patients after treatment with ranibizumab. Ophthalmology 2013;120:160–168. 6. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 7. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 2010;117:2134–2140. 8. Mantel I, Niderprim SA, Gianniou C, et al. Reducing the clinical burden of ranibizumab treatment for neovascular agerelated macular degeneration using an individually planned regimen. Br J Ophthalmol 2014;98:1192–1196. 9. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013;120:1046–1056. 10. Mantel I, Deli A, Iglesias K, Ambresin A. Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2013;251:697–704. 11. Jang L, Gianniou C, Ambresin A, Mantel I. Refractory subretinal fluid in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: visual acuity outcome. Graefes Arch Clin Exp Ophthalmol 2014 Sep 30. [Epub ahead of print]. 12. Gianniou C, Dirani A, Jang L, Mantel I. Refractory intraretinal or subretinal fluid in neovascular age-related macular degeneration treated with intravitreal ranizubimab: functional and structural outcome. Retina 2015 Feb 2. [Epub ahead of print]. 13. Kumar N, Marsiglia M, Mrejen S, et al. Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 2013;33:1605–1612. 14. Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 2013;97:1032–1035. 15. Chang AA, Li H, Broadhead GK, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology 2014;121:188–192. 16. Bakall B, Folk JC, Boldt HC, et al. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 2013;156:15–22.e11. 17. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular
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age-related macular degeneration. Am J Ophthalmol 2013; 156:29–35.e22. Grewal DS, Gill MK, Sarezky D, et al. Visual and anatomical outcomes following intravitreal aflibercept in eyes with recalcitrant neovascular age-related macular degeneration: 12month results. Eye (Lond) 2014;28:895–899. Comparison of Age-related Macular Degeneration Treatments Trials Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular agerelated macular degeneration: two-year results. Ophthalmology 2012;119:1388–1398. Gianniou C, Dirani A, Ferrini W, et al. Two-year outcome of an observe-and-plan regimen for neovascular age-related macular degeneration: how to alleviate the clinical burden with maintained functional results. Eye (Lond) 2015;29: 450–451. Schachat AP. Switching anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Am J Ophthalmol 2013;156:1–2.e1. Eghoj MS, Sorensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2012;96:21–23. Forooghian F, Cukras C, Meyerle CB, et al. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29:723–731. Tranos P, Vacalis A, Asteriadis S, et al. Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration. Drug Des Devel Ther 2013;7:485–490. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171–185. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF trap. Br J Ophthalmol 2008;92:667–668. Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 2003;44:3186–3193. Bottomley MJ, Webb NJ, Watson CJ, et al. Placenta growth factor (PlGF) induces vascular endothelial growth factor (VEGF) secretion from mononuclear cells and is coexpressed with VEGF in synovial fluid. Clin Exp Immunol 2000;119:182–188. Ferrone PJ, Anwar F, Naysan J, et al. Early initial clinical experience with intravitreal aflibercept for wet age-related macular degeneration. Br J Ophthalmol 2014;98(suppl 1): i17–i21. Mariani A, Deli A, Ambresin A, Mantel I. Characteristics of eyes with secondary loss of visual acuity receiving variable dosing ranibizumab for neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2011;249: 1635–1642. Rasmussen A, Bloch SB, Fuchs J, et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2013;120: 2630–2636. Bloch SB, la Cour M, Sander B, et al. Predictors of 1-year visual outcome in neovascular age-related macular degeneration following intravitreal ranibizumab treatment. Acta Ophthalmol 2013;91:42–47. Menghini M, Kurz-Levin MM, Amstutz C, et al. Response to ranibizumab therapy in neovascular. Klin Monbl Augenheilkd 2010;227:244–248.
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everal, Phase 3 multicenter pivotal trials have established intravitreal anti-vascular endothelial growth factor (VEGF) therapy as the gold standard treatment for neovascular age-related macular degeneration (nAMD). The anti-VEGF agent ranibizumab was introduced first1–3 followed by aflibercept several years later.4,5 Both agents potently inhibit VEGF and
have been shown to have equivalent efficacies, as determined by visual and structural outcomes.5 In most patients, injections can be administered less frequently than once a month using retreatment regimens, including the pro re nata approach,6 the treat-and-extend regimen,7 the “Observe and Plan” regimen,8 increased dosing,9 and fixed bimonthly retreatment.5 However, some patients still require monthly retreatment based on exudative signs at monthly examinations.10 Although these eyes may have a reasonable functional prognosis,11,12 clinicians tend to aim for a dry macula. To date, refractory or recurrent nAMD has been most often identified in patients treated with ranibizumab, because this drug has been used the longest in clinical practice. Several longitudinal studies in
From the *Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland; and †Medical Retina Clinic, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Irmela Mantel, MD, Fondation Asile des Aveugles, University Eye Hospital Jules-Gonin, Avenue de France 15, Case Postale 133, CH 1000 Lausanne 7, Switzerland; e-mail: [email protected]
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patients with refractory or recurrent nAMD have found that converting from ranibizumab or bevacizumab to aflibercept therapy seemed to have a beneficial effect on retinal structure13–18 and the number of required retreatments.17 However, the absence of a control group in these studies prohibits firm conclusions. It has been shown that disease activity (the amount of fluid) and retreatment needs may decrease over time,19,20 which may confound study results. Additional problems may include retrospective study designs, behavioral influences, and the possibility of regression to the mean.21 Prospective comparative trials, with well-defined treatment conditions, clear inclusion criteria, and balanced groups, would be required to understand whether a change of treatment improves the outcome. The aim of this study was to estimate the effect of converting to aflibercept therapy in a group of patients with nAMD who required monthly ranibizumab treatment, as compared with a balanced comparison group who continued with ranibizumab therapy. Methods We selected groups that were balanced for preceding treatment regimen, duration of anti-VEGF treatment, regimen, retreatment need, and demographics. To accomplish this, we performed an extension of a prospective clinical trial (protocol number 351/11, ethics committee VD) that was conducted over 2 years by the medical Retina Department of a single tertiary referral center (University Eye Hospital Jules-Gonin, Lausanne, Switzerland). The purpose of the prospective clinical trial was to evaluate the clinical value of an Observe and Plan treatment regimen for nAMD using intravitreal ranibizumab.8,20 This study was approved by the local ethics committee, and all study conduct adhered to the tenets of the Declaration of Helsinki. Applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research. All patients provided written informed consent for study participation. Patient Selection Patients were selected from a previously described nAMD study population. All patients had undergone the same prospective Observe and Plan retreatment regimen with ranibizumab.8 This previous prospective study included 115 eyes of 104 patients with treatmentnaive nAMD and active subfoveal choroidal neovascularization. All patients had a best-corrected visual acuity (BCVA) between 20/25 and 20/400, a maximum lesion
size of 12 disk areas, and had provided informed consent. The Observe and Plan retreatment regimen was fully described previously8 and is summarized below. After completion of a 24-month study period, patients who still needed monthly retreatment with ranibizumab based on optical coherence tomography (OCT) criteria (the presence of intraretinal or subretinal fluid) were eligible for the extension study. The need for monthly retreatment was based on the presence of refractory fluid when treatment was performed monthly or the recurrent fluid when the treatment interval was extended to 1.5 months. Of 25 eligible eyes, 21 eyes of 19 patients were randomized to either change to aflibercept treatment (Group A) or to remain on ranibizumab therapy (Group R). After converting to aflibercept or continuing on ranibizumab, the retreatment regimen remained the same, starting with 3 monthly injections and then extending the treatment intervals according to OCT criteria under an ongoing Observe and Plan regimen for 12 months. Clinical Investigations At each study visit, the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA and intraocular pressure were measured. Slit-lamp examination, dilated fundus examination, and spectral domain OCT were performed. The original 24-month study spectral domain OCT scans were obtained using the macular cube scan protocol (512 · 126 scan) of the Cirrus OCT (Carl Zeiss Meditec, Inc, Oberkochen, Germany). However, spectral domain OCT scans in the extension study were predominantly obtained with the 6 · 6-mm cube scan protocol (49 line scans) on the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography and indocyanine green angiography (Topcon TRC-50IX, Tokyo, Japan) were performed before initiating treatment. Fluorescein angiography was repeated approximately every year. “Observe and Plan” Treatment Regimen The Observe and Plan regimen is an interval-based variable dosing regimen. The methodology of the Observe and Plan treatment regimen has been fully described elsewhere.8 The concept of this regimen is to first measure and then to plan the ideal retreatment interval in a fixed but individualized retreatment regimen. After initiation of treatment with 3 monthly loading doses of intravitreal ranibizumab, each patient’s treatment-recurrence interval was determined during an observation phase. The resulting interval was then shortened by 2 weeks for the series of subsequently
SWITCH OR NOT IN REFRACTORY AMD MANTEL ET AL
planned injections. After 3 planned injections, patients were again assessed to allow for adjustment of the treatment interval every 6 months at the latest (patients were assessed after 2 planned injections if the interval was longer than 2 months). If signs of exudation were detected on OCT images (intraretinal or subretinal fluid) or fundus examination (hemorrhage), future treatment intervals were shortened by 2 weeks. Otherwise, the treatment intervals were lengthened by 2 weeks. The shortest allowed interval was 1 month, and the longest was 3 months. Clinical Outcome Analysis The outcome measures included the mean retreatment interval over a 12-month study period (overall third year of study participation) and the proportion of eyes achieving a longer retreatment interval than in the preceding 6 months (individual mean). In addition, we analyzed the proportion of patients with a dry retina (as determined with qualitative OCT image criteria), the number of injections, and change of BCVA. Quantitative OCT parameters (e.g., retinal thickness) were not examined because of frequent changes in OCT instrumentation during the study period. Statistical Evaluation The statistical analysis is mainly descriptive because of the limited power of the small sample size. For data at the end point of the study (BCVA), the last available measures were carried forward because of visits that were not performed monthly. Baseline for Group A was the time of the conversion to aflibercept treatment (approximately the end of the original 24-month study, depending on the time of the visit). Baseline for Group R, who continued with ranibizumab treatment, was Month 24. Treatment intervals that carried over into another treatment period (e.g., Year 4) were taken into account, but only according to the proportion of time within the evaluation period. Except for descriptive statistics, explorative analyses were performed using the Yates corrected chisquare test for categorical data and the Mann–Whitney U test for continuous variables. Statistical significance was defined as P , 0.05. Results Study Population Twenty-one eyes of 19 patients were ultimately included in this extension study. This represented 20% of the 105 eyes that had completed the previous
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24-month trial. During the 1-year study period (the third year of treatment), 10 eyes (9 patients) were converted to intravitreal aflibercept (Group A) and 11 eyes (10 patients) received intravitreal ranibizumab (Group R). All patients agreed to continue on the Observe and Plan regimen as an extension of the initial 24-month ranibizumab trial. Characteristics of patients in the 2 study groups were well balanced at baseline (Table 1). There was no significant difference between groups in age, BCVA before anti-VEGF therapy, BCVA improvement during the first 24 months of treatment, AMD lesion characteristics (e.g., pigment epithelium detachment), number of injections, or previous duration of treatment. Additionally, there was no difference in the proportion of eyes with persistent fluid on OCT (Group A, 70%; Group R, 73%) or that required monthly retreatment because of exudative recurrence under longer treatment intervals (Group A, 30%; Group R, 27%). Treatment Outcomes A summary of the treatment outcomes is given in Table 2. The mean retreatment interval during 12 months of this study was 1.13 months (standard deviation [SD] 0.14 months) in Group A and 1.14 months (SD 0.18 months) in Group R. Approximately half of the eyes in each group had a longer retreatment interval during the study period than during 6 months before this extension study (treatment months, 18–24). The number of eyes that attained a dry macula during the 12-month study period was 4 of 10 eyes (40%) in Group A and 4 of 11 eyes (36%) in Group R. The mean number of injections was 10.7 (SD 1.2) and 10.7 (SD 1.5) in Groups A and R, respectively. Mean visual acuity decreased by 2.0 ETDRS letters (SD 3.0) in Group A and increased by 0.5 ETDRS letters (SD 2.5) in Group R, a difference that was nearly significant (P = 0.07). The preceding BCVA data was therefore compared in a post hoc analysis. The change in BCVA from anti-VEGF treatment initiation to baseline (treatment Months 0–24) was not different (see also baseline characteristics, Table 1), but the immediate response to the ranibizumab loading dose at the initiation of anti-VEGF therapy was significantly poorer in Group A (−1.3 letters, SD 12.0) than in Group R (+9.6 letters, SD 11.0) (P = 0.026). Discussion In this study, we explored the effect of converting patients with nAMD from ranibizumab to aflibercept therapy and compared these results to patients with nAMD continuing on ranibizumab therapy. All
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 1 Table 1. Patient Characteristics at Baseline
Age, years BCVA before anti-VEGF treatment, Snellen (ETDRS letters; SD) BCVA change between therapy initiation and baseline, ETDRS letters Previous treatment duration, months Total number of previous injections Number of injections during the 6 months before baseline Mean interval injections during the 6 months before baseline Persistent fluid on OCT, % Angiographic type of CNV Predominantly classic Minimally classic Occult RAP Presence of PED, %
All Studied Patients
Group A
Group R
N = 21 Eyes
N = 10 Eyes
N = 11 Eyes
76.0 (23.5) 20/50−1 (64.4; 14.9)
77.0 (25.0) 20/50 (65.2; 11.5)
75.2 (23.3) 20/50−1 (63.6; 17.9)
6.6 (15.1)
5.6 (15.8)
7.5 (15.1)
24.3 (2.6) 20.7 (2.9) 5.4 (0.6)
24.6 (3.9) 21.3 (2.6) 5.4 (0.7)
24.0 (0) 20.1 (3.2) 5.3 (0.5)
1.1 (0.1)
1.1 (0.2)
1.1 (0.1)
15 (71)
7 (70)
8 (73)
4 4 12 1 9 (43)
1 2 7 0 5 (50)
3 2 5 1 4 (36)
All patients had nAMD that required monthly ranibizumab retreatment after 2 years of ranibizumab therapy. Data are presented as mean (SD), where applicable. CNV, choroidal neovascular membrane; Group A, group aflibercept; Group R, group ranibizumab; PED, pigment epithelium detachment; RAP, retinal angiomatous proliferation.
included patients required monthly retreatment at baseline. In addition, all patients entered the study at the same time point of their overall treatment duration, which was 2 years after initiation of ranibizumab therapy, under the same interval-based regimen. The well-balanced groups showed very similar results in mean treatment interval, proportion of patients with longer intervals, proportion with dry maculae, mean number of injections, and BCVA. The small sample size does not allow for a statistical conclusion; therefore, this study should be considered an exploratory pilot study. The similarity of the results in the two groups may contradict the frequently reported benefit of converting to aflibercept in cases of refractory or recurrent nAMD.13–18
Our current understanding of the usefulness of changing from ranibizumab to aflibercept in refractory or recurrent cases relies on noncomparative switch studies, all but one15 of which have been retrospective.13–18 Although these studies are interesting and clearly suggest a benefit in converting to aflibercept, the absence of a well-balanced control group makes them difficult to interpret because of the potential effect of evolution over time, the possibility of regression to the mean, inhomogeneous times of treatment change, differences in reported outcomes, and uncertainty regarding the adequacy of the previous treatment.21 Thus, even a noticeable improvement found in a longitudinal noncomparative switch study might not provide reliable data with which to make conclusions about the
Table 2. Anatomical, Functional, and Treatment Results of the 1-Year Study, Corresponding With the Third Year of AntiVEGF Treatment for AMD That Required Monthly Ranibizumab Retreatment After 2 Years of Ranibizumab Therapy
Retreatment interval, months (SD) Eyes with increased treatment interval, % Eyes with dry macula at some time during the study (Y3), % Number of injections (SD) BCVA change from baseline, ETDRS letters (SD)
All Patients
Group A
Group R
N = 21 Eyes
N = 10 Eyes
N = 11 Eyes
1.1 (0.2) 11 (52) 8 (38)
1.1 (0.1) 6 (60) 4 (40)
1.1 (0.2) 5 (45) 4 (36)
10.7 (1.3) −0.7 (3.0)
10.7 (1.2) −2.0 (3.0)
10.7 (1.5) 0.5 (2.5)
The groups either continued on ranibizumab or converted to aflibercept. Baseline, the time of treatment change (Group A) or Month 24 of the total treatment duration (Group R); Group A, group aflibercept; Group R, group ranibizumab; Y3, Year 3 (the 12-month study duration, corresponding with the third year of each patient’s treatment period).
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usefulness of medication change. The assumption of no change under continuation of the same medication could be incorrect; it would not correspond with the observation that retreatment needs generally decrease over time.19,20 Eyes with the greatest need for retreatment tend to have longer treatment intervals over time, even when continuing with the same drug (as shown in the 24-month results of the Observe and Plan study).20 In addition, Jang et al11 in their study of ranibizumab reported that refractory subretinal fluid may disappear at any time during ongoing monthly treatment with the same medication. Therefore, time is clearly a factor in the outcome. To properly assess the effect of a treatment change on outcome, a prospective comparative study with half of the patients remaining on the original treatment and half of them changing to a different one is required. However, several study conditions should be implemented. First, the previous treatment regimen should be standardized, maintaining uniform timelines for retreatment; longer intervals between injections increase the likelihood of fluid in the retina. In particular, the last treatment intervals before the medication change should be carefully planned, because they influence the amount of fluid present at the time of the change. The ideal situation would be the end of a prospective clinical trial. Second, the times of treatment follow-up should be uniform, because the behavior of nAMD can change over the years. Third, the type of retreatment regimen should be standardized. Fourth, the demographic and lesion characteristics of the study groups should be balanced. To the best of our knowledge, our study is the only one that has fulfilled these requirements. Unfortunately, our sample size is too small to show a statistically significant effect. However, as the only comparative data of well-balanced comparison groups available to date, it may serve as a pilot study, allowing for power calculations for future prospective comparative switch trials. Given the similarities in structural and treatment characteristics between our study groups, it is evident that the sample size of each group would need to be .100 to demonstrate a statistical difference. If the study were performed at the end of a previous prospective trial with the same recruitment proportion (20%) as in our study, the previous clinical trial would require more than 1,000 patients. The similar results in our two study groups were somewhat surprising to us. Not only did we expect to see some difference based on previous switch reports and because of a possible ranibizumab tachyphylaxis,22–24 but a switch benefit also seemed likely because of the higher binding affinity of aflibercept25 and its theoretically longer ligand-binding activity.26
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In addition, the placental growth factor antagonism of aflibercept could play a role in the treatment of nAMD. Placental growth factor has been identified in the choroidal neovascularization process,27 and it stimulates production of VEGF.28 However, the VIEW studies showed no differences in retreatment needs, change in central retinal thickness, or in visual outcomes for a general nAMD cohort.4 A recent study also found that converting from ranibizumab to aflibercept did not reduce the need for retreatment without previous selection of refractory cases.29 The Observe and Plan regimen used in this study is an interval-based regimen that seems to be useful in capturing changing retreatment needs over time. However, because of the relatively delayed reassessment visits (every 3–6 months), a 12-month observation period was needed to detect these changes. One parameter that tended to be different between the aflibercept and ranibizumab groups was the change in visual acuity over the 12-month study period (the third treatment year). Group A tended to have poorer visual outcomes than Group R. We assume that this difference resulted from the lower BCVA gain in Group A 3 months after treatment initiation; this has been shown to be a risk factor for later BCVA loss.30–33 A poor initial response to intravitreal anti-VEGF therapy may indicate more severe degenerative changes. Our study has some important limitations. The sample size is too small for reliable statistical comparison between the groups; therefore, our study may be considered a pilot comparative study. In addition, we could not obtain homogenous quantitative automated OCT measurements because of frequent changes of OCT machines during the study period. Finally, this study does not distinguish between phenotypical subgroups, which might show different sensitivities to the drugs. In conclusion, this comparative pilot study suggests that in patients with nAMD requiring monthly retreatment with ranibizumab, there may be little clinical difference between changing to aflibercept and remaining on ranibizumab treatment. Although the small numbers prohibit any statistical conclusions, the similar results in the groups may challenge reports of the benefit of changing treatment. Wellconstructed prospective studies with large and balanced groups would be needed to determine the benefit of switching from ranibizumab to aflibercept in patients with nAMD. Key words: anti-VEGF therapy, ranibizumab, aflibercept, neovascular age-related macular degeneration, observe and plan regimen.
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