- Email: [email protected]
One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration
6. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146(4):496–500. 7. Ikuno Y, Maruko I, Yasuno Y, et al. Reproducibility of retinal and choroidal thickness measurements in enhanced depth imaging and high-penetration optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52(8):5536–5540.
One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration EDITOR: WE READ WITH GREAT INTEREST THE ARTICLE ENTITLED
‘‘One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration’’ by Arcinue and associates.1 We would like to congratulate the authors for conducting such a thorough study exploring the effects of intravitreal aflibercept administered every 8 weeks in a pro re nata regimen in patients affected by neovascular age-related macular degeneration (nAMD) and showing resistance to ranibizumab or bevacizumab injections. However, we have a few queries regarding the methodology. The question of the most appropriate definition of resistant patients has already been addressed in previous studies considering patients with refractory, persistent, and resistant conditions or eyes displaying a frequent recurrence of the condition during anti–vascular endothelial growth factor (anti-VEGF) treatment.2–4 In the current study, Arcinue and associates defined patients with multiple recurrences or persistence of exudation as resistant. More specifically, they excluded patients who had responded excellently to anti-VEGF agents and included only eyes that they considered ‘‘truly resistant.’’ It is very difficult to tell the difference between patients who are ‘‘truly resistant’’ and simply resistant. In our standard clinical practice we usually observe 3 different responses. First of all, as luck would have it, most of the eyes we deal with show a complete response to anti-VEGF, usually indicated by a complete resolution of the fluid after the treatment, which can recur over the follow-up both frequently and rarely. Then there are patients who do not respond to the treatment from the beginning and can truly be defined as ‘‘nonresponders.’’ Lastly, other patients may also display an absence of response after the initial success of the anti-VEGF therapy, and this can be ascribed to the tachyphylaxis phenomenon. There is currently no clear agreement on the parameters to be adopted to define either the presence or the absence of response, including aspects such as visual acuity change, time or amount of fluid resolution, or a combination of functional and morphologic parameters. 996
Regarding anti-VEGF resistance, we propose that the concept be divided into 3 aspects: first, functional resistance, characterized by the complete resolution of fluid, with no visual acuity change within at least 2 Early Treatment Diabetic Retinopathy Study (EDTRS) lines5; second, anatomic resistance, characterized by visual acuity improvement of at least 2 lines,5 in which fluid is detected; and third, full resistance, with visual acuity deterioration and/or no visual acuity change of at least 2 EDTRS lines5 in association with persistence of fluid. Arcinue and associates’ definition of resistance based on multiple recurrences is not clear enough, and in our opinion the median number of 2 recurrences does not seem to be a real sign of resistance. In light of these assumptions, the 32 eyes with persistent fluid collection despite the at least 5-monthly consecutive ranibizumab/bevacizumab injections might also qualify as resistant. The remaining 31 eyes should be considered patients with recurrences and the effects of switching to aflibercept injections should be analyzed separately and compared with studies considering the switching therapy in patients with nAMD responders to other anti-VEGF agents, as for example in the ASSESS trial.6 PIERLUIGI IACONO
Rome, Italy MAURIZIO BATTAGLIA PARODI FRANCESCO BANDELLO
Milano, Italy THE AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE Form for Disclosure of Potential Conflicts of Interest. Financial Disclosures: F. Bandello is an advisory board member for Allergan (USA), Novartis Pharmaceuticals Corporation (Switzerland), FarmilaThea (France), Bayer Schering Pharma (Germany), Pfizer, Alcon, Bausch and Lomb (USA), Genentech (USA), Alimera Sciences (USA), SanofiAventis (France), Thrombogenics (USA), Hoffmann-La Roche (Switzerland), and Novagali Pharma (France); P. Iacono is a consultant for Novartis Pharmaceutical Corporation (Switzerland). Funding/Support: The research for this paper was partially supported by the Ministry of Health and Fondazione Roma.
REFERENCES
1. Arcinue CA, Ma F, Barteselli G, Sharpsten L, Gomez ML, Freeman WR. One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 2015;159(3):426–436.e2. 2. 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(1): 15–22.e1. 3. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular agerelated macular degeneration. Am J Ophthalmol 2013;156(1): 29–35.e2. 4. Schachat AP. Switching anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Am J Ophthalmol 2013;156(1):1–2.e1.
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2015
5. Patel PJ, Chen FK, Rubin GS, Tufail A. Intersession repeatability of visual acuity scores in age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49(10):4347–4352. 6. Singh RP, Srivastava S, Ehlers JP, Bedi R, Schachat AP, Kaiser PK. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 2014;98(Suppl 1):i22–27.
REPLY WE THANK IACONO AND ASSOCIATES FOR THEIR INTEREST
in our article, which included wet age-related macular degeneration (AMD) patients that had multiple recurrences or persistence of exudation owing to contingent negative variation (CNV) activity. We felt it important to exclude eyes that had responded excellently to anti– vascular endothelial growth factor (VEGF) agents in terms of CNV activity, and included only eyes that we considered ‘‘truly resistant.’’ There is a significant population of patients who respond well to anti-VEGF agents and remained dry on optical coherence tomography (OCT) and inactive on fluorescein angiography for years; we felt those should be excluded and may fall under Iacono and associates’ classification as ‘‘complete responders.’’ Eyes with multiple recurrences might be termed ‘‘transient responders.’’ We distinguished such eyes from eyes that had persistent fluid, or what Iacono and associates define as ‘‘nonresponders.’’ We agree that the terms ‘‘responder’’ and ‘‘nonresponder’’ for wet AMD patients are confusing and there is no consensus about the meaning of ‘‘resistance’’ to antiVEGF therapy. In the HARBOR trial, some 20% of wet AMD patients required a large number of intravitreal
VOL. 159, NO. 5
ranibizumab injections before experiencing a response to the therapy. One may call them ‘‘nonresponders,’’ while others may call them ‘‘slow or delayed responders.’’ In summary, patient responses to anti-VEGF agents are exceedingly varied, and it is hard to have set criteria when we are dealing with numerous parameters such as presence or absence of response, quality and degree of response, initial or delayed response, visual acuity gain, decrease in central retinal thickness, or a combination of functional and anatomic parameters. However, the response must be qualified and defined in more detail, whether complete, incomplete, or nonresponder, and whether the response is early or delayed, sustained or transient. In our study, we did not analyze separately the eyes with recurrent vs persistent fluid. We thank Iacono and associates for their suggestion, but at this point we think that only a randomized controlled trial of switching among different anti-VEGF agents can prove whether tachyphylaxis is really the culprit behind resistance; but there does seem to be some benefit of aflibercept on bevacizumab or ranibizumab incomplete responders. CHERYL A. ARCINUE FEIYAN MA GIULIO BARTESELLI LUCIE SHARPSTEN MARIA LAURA GOMEZ WILLIAM R. FREEMAN
La Jolla, California
CONFLICT OF INTEREST DISCLOSURES: SEE THE ORIGINAL article for any disclosures of the authors.
CORRESPONDENCE
997
One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration EDITOR: WE READ WITH GREAT INTEREST THE ARTICLE ENTITLED
‘‘One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration’’ by Arcinue and associates.1 We would like to congratulate the authors for conducting such a thorough study exploring the effects of intravitreal aflibercept administered every 8 weeks in a pro re nata regimen in patients affected by neovascular age-related macular degeneration (nAMD) and showing resistance to ranibizumab or bevacizumab injections. However, we have a few queries regarding the methodology. The question of the most appropriate definition of resistant patients has already been addressed in previous studies considering patients with refractory, persistent, and resistant conditions or eyes displaying a frequent recurrence of the condition during anti–vascular endothelial growth factor (anti-VEGF) treatment.2–4 In the current study, Arcinue and associates defined patients with multiple recurrences or persistence of exudation as resistant. More specifically, they excluded patients who had responded excellently to anti-VEGF agents and included only eyes that they considered ‘‘truly resistant.’’ It is very difficult to tell the difference between patients who are ‘‘truly resistant’’ and simply resistant. In our standard clinical practice we usually observe 3 different responses. First of all, as luck would have it, most of the eyes we deal with show a complete response to anti-VEGF, usually indicated by a complete resolution of the fluid after the treatment, which can recur over the follow-up both frequently and rarely. Then there are patients who do not respond to the treatment from the beginning and can truly be defined as ‘‘nonresponders.’’ Lastly, other patients may also display an absence of response after the initial success of the anti-VEGF therapy, and this can be ascribed to the tachyphylaxis phenomenon. There is currently no clear agreement on the parameters to be adopted to define either the presence or the absence of response, including aspects such as visual acuity change, time or amount of fluid resolution, or a combination of functional and morphologic parameters. 996
Regarding anti-VEGF resistance, we propose that the concept be divided into 3 aspects: first, functional resistance, characterized by the complete resolution of fluid, with no visual acuity change within at least 2 Early Treatment Diabetic Retinopathy Study (EDTRS) lines5; second, anatomic resistance, characterized by visual acuity improvement of at least 2 lines,5 in which fluid is detected; and third, full resistance, with visual acuity deterioration and/or no visual acuity change of at least 2 EDTRS lines5 in association with persistence of fluid. Arcinue and associates’ definition of resistance based on multiple recurrences is not clear enough, and in our opinion the median number of 2 recurrences does not seem to be a real sign of resistance. In light of these assumptions, the 32 eyes with persistent fluid collection despite the at least 5-monthly consecutive ranibizumab/bevacizumab injections might also qualify as resistant. The remaining 31 eyes should be considered patients with recurrences and the effects of switching to aflibercept injections should be analyzed separately and compared with studies considering the switching therapy in patients with nAMD responders to other anti-VEGF agents, as for example in the ASSESS trial.6 PIERLUIGI IACONO
Rome, Italy MAURIZIO BATTAGLIA PARODI FRANCESCO BANDELLO
Milano, Italy THE AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE Form for Disclosure of Potential Conflicts of Interest. Financial Disclosures: F. Bandello is an advisory board member for Allergan (USA), Novartis Pharmaceuticals Corporation (Switzerland), FarmilaThea (France), Bayer Schering Pharma (Germany), Pfizer, Alcon, Bausch and Lomb (USA), Genentech (USA), Alimera Sciences (USA), SanofiAventis (France), Thrombogenics (USA), Hoffmann-La Roche (Switzerland), and Novagali Pharma (France); P. Iacono is a consultant for Novartis Pharmaceutical Corporation (Switzerland). Funding/Support: The research for this paper was partially supported by the Ministry of Health and Fondazione Roma.
REFERENCES
1. Arcinue CA, Ma F, Barteselli G, Sharpsten L, Gomez ML, Freeman WR. One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 2015;159(3):426–436.e2. 2. 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(1): 15–22.e1. 3. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular agerelated macular degeneration. Am J Ophthalmol 2013;156(1): 29–35.e2. 4. Schachat AP. Switching anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Am J Ophthalmol 2013;156(1):1–2.e1.
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2015
5. Patel PJ, Chen FK, Rubin GS, Tufail A. Intersession repeatability of visual acuity scores in age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49(10):4347–4352. 6. Singh RP, Srivastava S, Ehlers JP, Bedi R, Schachat AP, Kaiser PK. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 2014;98(Suppl 1):i22–27.
REPLY WE THANK IACONO AND ASSOCIATES FOR THEIR INTEREST
in our article, which included wet age-related macular degeneration (AMD) patients that had multiple recurrences or persistence of exudation owing to contingent negative variation (CNV) activity. We felt it important to exclude eyes that had responded excellently to anti– vascular endothelial growth factor (VEGF) agents in terms of CNV activity, and included only eyes that we considered ‘‘truly resistant.’’ There is a significant population of patients who respond well to anti-VEGF agents and remained dry on optical coherence tomography (OCT) and inactive on fluorescein angiography for years; we felt those should be excluded and may fall under Iacono and associates’ classification as ‘‘complete responders.’’ Eyes with multiple recurrences might be termed ‘‘transient responders.’’ We distinguished such eyes from eyes that had persistent fluid, or what Iacono and associates define as ‘‘nonresponders.’’ We agree that the terms ‘‘responder’’ and ‘‘nonresponder’’ for wet AMD patients are confusing and there is no consensus about the meaning of ‘‘resistance’’ to antiVEGF therapy. In the HARBOR trial, some 20% of wet AMD patients required a large number of intravitreal
VOL. 159, NO. 5
ranibizumab injections before experiencing a response to the therapy. One may call them ‘‘nonresponders,’’ while others may call them ‘‘slow or delayed responders.’’ In summary, patient responses to anti-VEGF agents are exceedingly varied, and it is hard to have set criteria when we are dealing with numerous parameters such as presence or absence of response, quality and degree of response, initial or delayed response, visual acuity gain, decrease in central retinal thickness, or a combination of functional and anatomic parameters. However, the response must be qualified and defined in more detail, whether complete, incomplete, or nonresponder, and whether the response is early or delayed, sustained or transient. In our study, we did not analyze separately the eyes with recurrent vs persistent fluid. We thank Iacono and associates for their suggestion, but at this point we think that only a randomized controlled trial of switching among different anti-VEGF agents can prove whether tachyphylaxis is really the culprit behind resistance; but there does seem to be some benefit of aflibercept on bevacizumab or ranibizumab incomplete responders. CHERYL A. ARCINUE FEIYAN MA GIULIO BARTESELLI LUCIE SHARPSTEN MARIA LAURA GOMEZ WILLIAM R. FREEMAN
La Jolla, California
CONFLICT OF INTEREST DISCLOSURES: SEE THE ORIGINAL article for any disclosures of the authors.
CORRESPONDENCE
997