Use of Aflibercept in cases of recurrent or refractory neovascular AMD previously treated with other antiangiogenic drug: anatomo-functional outcomes

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1 Use of Aflibercept in cases of recurrent or refractory neovascular AMD previously treated with other antiangiogenic drug: anatomo-functional outcomes Daniel E. Charles, MD, Martin Charles, MD, Gisela Jelusich, MD and Tamara Zompa, MD ASRS 204 Centro Oftalmológico Dr. Charles and Fundación VER, Buenos Aires, Argentina. Table. Statistical data Pre- and post Eylia Background.82 ± 7.26 AVE IJECTIOS OF AAG PRE-EYLIA Age related macular degeneration (AMD) is the most common cause of irreversible blindness in the industrial countries. Despite the fact that bevacizumab and ranibizumab have had a significant impact on preserving vision (), some cases that displayed positive outcomes at first, later became resistant to further treatment, developing recurrent exudation associated to vision loss.(2) Tachyphylaxis is considered to be the most probable cause of this issue. Increasing drug dose, frequency of treatment, or even switching to a different antiangiogenic drug are three posible ways to adress this problem. (3) 00 Bevacizumab 63.5% (24/) ranibizumab 34.2% (3/) Pre Eylia Post Eylia 40 Table and graphic 2. T test Pairs 20 0 Subretinal Fluid CORRELATIOS BCVA pre EYLIA BCVA pre EYLIA Pearson correlation Sig. (bivar.) Purpose ** Sig. (bivar.) To report the visual and anatomical outcomes of patients with refractory or recurrent neovascular AMD who were switched from ranibizumab or bevacizumab to aflibercept treatment. DEP Pearson correlation BCVA post EYLIA Intraretinal Fluid BCVA post EYLIA **The correlation is significative at level 0.0 (bivar.). Table and graphic 3. Pearson correlation for changes in CRT Methods Retrospective consecutive observational case series of (thirty eight) eyes with refractory or recurrent neovascular age-related macular degeneration (AMD) previously treated with bevacizumab and/or ranibizumab. In all cases, the patients were switched to aflibercept, receiving a regimen of at least 3 monthly intravitreal injections. All cases received a complete ophthalmic examination, including best corrected visual acuity (BCVA), central macular thickness (CMT) on Optical Coherence Tomography (OCT), numbers of previous injections and demographic data were collected. All were patients older than fifty years. Cases with severe scarring or macular atrophy were excluded. The data was collected in an Excel sheet and analyzed with the IBM SPSS Statistic 9 Program. Graphic. Percentage of patients with different sites with fluid, Pre and Pos Switch Correlations CRT PRE CRT POST CRT PRE Pearson correlation.70** Sig. (bivar) CRT POST Pearson correlation.70** Sig. (bivar) **. The correlation is significative at level 0,0 (bivar). Table 4. 5 examples of anatomical changes and visual recovery Case Case 2 Case 3 Case 4 Case 5 Discussion In this case series we attempted to study the anatomofunctional response to a new antiangiogenic drug, in patients previously treated with bevacizumab or ranibizumab. These patients who had shown a positive initial response to these drugs, subsequently began to display resistance to both of them, thus, resulting in recurrence of exudation. A significant average decrease in CMT was found. However, subretinal fluid, and presence of PEDs proved more difficult to improve as individual parameters. After three injections of aflibercept, in type neovascularization cases, PED showed a change as far as height, but not in regards to the maximum diameter of the base. Kumar and colleagues (3) reported that the tissue located between Bruch`s membrane and the RPE consists of serous, hemorrhagic, and fibrocellular material. We are inclined to agree with this theory. Treatment with antivegfs affects the serous, hemorrhagic and exudative components of the sub RPE tissue, but the mature fibrocellular part of the membrane could be resistant to the treatment (at least, to only the first three injections). So, these cases do not respond in a similar manner to those reported by clinical trials that treat naïve cases.(4) We certainly need extended time of follow up of these patients to asses the possibility of tachyphylaxis with this antiangiogenic drug (5). Conclusions First visit Switching patients with chronic or recurrent PRE switch Results Total n IVI of AAGs pre-switch The mean age was 74,63 years (range ys.). There were 20 (52.6%) female and 8 (47.4%) male. The total mean number of prior injections with ranibizumab or bevacizumab was.82 (range 4-35).(Table ) After three monthly injections of aflibercept, we evaluated the presence, reduction or absence of the different sites of fluid in exudative AMD and we noted a reduction of the subretinal fluid from 8.6% to 60.5%; a reduction in the intraretinal fluid from 44.7% to 2.%, despite the persistence of pigment epithelial detachment, with minimal changes from 97.4% to (Graphic ) There was a significant decrease in the CMT from 25.3 microns to microns (Table and graphic 3), with a moderate Pearson correlation (0.747) in the change of the BCVA. (Table and graphic 2) In the T Test the differences in the 3 pairs data (BCVA, CMT, AVE CMT) were highly correlated (p< 0.00). (See Table 4). Pos-switch 28 (ranibiz. X 5 + bevaciz. x 23) 4 ( 2 ranibiz (3 ranibizu (0 ranibiz ( 8 ranibiz + 8 The mechanism by wich Aflibercept can benefit patients with previous resistance to Ranibizumab or Bevacizumab is still unknown. References 2 3 BCVA pre pos switch neovascular AMD to aflibercept results in improved anatomic outcomes and visual stability, thus allowing injection intervals to be extended progressively and requiring more than 3 first injections. 20/40-20/25 20/00 20/40 20/00 20/80 20/80-20/30 20/200 20/50. JC Folk, EM Stone, Ranibizumab therapy for neovascular age-related macular degeneration. England J Med (7): S Schaal, HJ Kaplan, TH Tezel, Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherpay in age related macular degeneration? Ophthalmmology 2008; 5(2): Kumar, M Marsiglia, S Mrejen, A Tien-Chin Fung, J Slatker, J Sorenson, KB Freund. Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patient with neovascular age-related macular degeneration. Retina 203, 0: Heier JS, Brown DM, Chong V, et al; VIEW and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology. 202;9(2): , appendices Fung AE. Results of the ROLL study: Conversion of PEDs from 2 mg ranibizumab to 2 mg aflibercept. Paper presented at: Angiogenesis, Exudation, and Degeneration 204; February 8, 204; Miami, FL.

2 *p<0.005: very significant correlation **p<0.00: highly significant correlation To report the visual and anatomical outcomes of patients with refractory or recurrent neovascular AMD who were switched from ranibizumab or bevacizumab to aflibercept. Daniel E. Charles, MD; Martin Charles, MD; Gisela Jelusich, MD and Tamara Zompa MD.

3 Retrospective consecutive observational case series of (thirty eight) eyes with refractory or recurrent neovascular age-related macular degeneration (AMD) previously treated with bevacizumab or ranibizumab. In all cases, the patients were switched to aflibercept, receiving a regimen of at least 3 monthly intravitreal injections.(ivi) All cases received a complete ophthalmic examination, including best corrected visual acuity (BCVA), central macular thickness (CMT) on Optical Coherence Tomography (OCT), numbers of previous injections and demographic data were collected. All were patients older than fifty years. Cases with severe scarring or macular atrophy were excluded. The data was collected in an Excel sheet and analyzed with the IBM SPSS Statistic 9 Program. Daniel E. MD, Martin Centro MD; Gisela Jelusich, MD and Tamara Oftalmológico Dr. Charles, Buenos Aires, Argentina Zompa MD.

4 The mean age was 74,63 years (range ys.). There were 20 (52.6%) female and 8 (47.4%) male. The total mean number of prior injections with ranibizumab or bevacizumab was.82 (range 4-35). After three monthly injections of aflibercept, we evaluated the presence, reduction or absence of the different sites of fluid in exudative AMD and we noted a reduction of the subretinal fluid from 8.6% to 60.5%; a reduction in the intraretinal fluid from 44.7% to 2.%, despite the persistence of pigment epithelial detachment, with minimal changes from 97.4% to (Graphic ) Graphic Pre Eylia Post Eylia There was a significant decrease in the CMT from 25.3 microns to microns (Table and graphic 3), with a moderate Pearson correlation (0.747) in the change of the BCVA. (Table and graphic 2) In the T Test the differences in the 3 pairs data (BCVA, CMT, AVE CMT) were highly correlated (p< 0.00). (See Table 4) 0 Subretinal Fluid Intraretinal Fluid DEP Table and Graphic 3 CORRELATIOS BCVA pre EYLIA BCVA post EYLIA BCVA pre EYLIA Pearson correlation.745 Sig. (bivar.) BCVA post EYLIA Pearson correlation.747 ** Sig. (bivar.) **. **The correlation is significative at level 0.0 (bivar.). Daniel E. Charles, MD, Martin Charles, MD; Gisela Jelusich, MD and Tamara Zompa MD.

5 Case Case 2 Case 3 Case 4 Case 5 4 ( 2 ranibiz (3 ranibizu (0 ranibiz ( 8 ranibiz + 8 First visit PRE switch Total n IVI of 28 AAGs pre- (ranibiz. X 5 + bevaciz. Switch x 23) Pos-switch 2 3 BCVA pre pos switch Daniel E. 20/40-20/25 20/00 20/40 MD, Martin Centro 20/00 20/80 MD; Gisela 20/80-20/30 Jelusich, 20/200 20/50 MD and Tamara Oftalmológico Dr. Charles, Buenos Aires, Argentina Zompa MD.

6 In this case series we attempted to study the anatomofunctional response to a new antiangiogenic drug, in patients previously treated with bevacizumab or ranibizumab. These patients, who had shown a positive initial response to these drugs, subsequently began to display resistance to both of them, thus, resulting in recurrence of exudation. A significant average decrease in CMT was found. However, subretinal fluid, and presence of PEDs proved more difficult to improve as individual parameters. After three injections of aflibercept, in type neovascularization cases, PED showed a change as far as height, but not in regards to the maximum diameter of the base. Kumar and colleagues (3) reported that the tissue located between Bruch s membrane and the RPE consists of serous, hemorrhagic, and fibrocellular material. We are inclined to agree with this theory. Treatment with antivegfs affects the serous, hemorrhagic and exudative components of the sub RPE tissue, but the mature fibrocellular part of the membrane could be resistant to the treatment (at least, to only the first three injections). So, these cases do not respond in a similar manner to those reported by clinical trials that treat naïve cases.(4) We certainly need extended time of follow up of these patients to asses the possibility of tachyphylaxis with this antiangiogenic drug (5). Daniel E. Charles, MD, Martin Charles, MD; Gisela Jelusich, MD and Tamara Zompa MD.

7 Switching patients with chronic or recurrent neovascular AMD to aflibercept results in improved anatomic outcomes and visual stability, thus allowing injection intervals to be extended progressively and requiring more than 3 first injections. The mechanism by wich Aflibercept can benefit patients with previous resistance to Ranibizumab or Bevacizumab is still unknown. We certainly need extended time of follow up of these patients to asses the posibility of tachyphylaxis with this antiangiogenic drug too. Daniel E. Charles, MD, Martin Charles, MD; Gisela Jelusich, MD and Tamara Zompa MD.