The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 13, 2019

Clinical Risk Factors for Poor Anatomic Response to Ranibizumab in Neovascular Age-Related Macular Degeneration§



Josef Guber*, 1, Tatjana Josifova 2, Paul Bernhard Henrich 2, Ivo Guber 3
1 Sutton Eye Hospital, Epsom and St Helier University Hospitals, London, UK
2 Department of Ophthalmology, University of Basel, Basel, Switzerland
3 Eye Clinic, Cantonal Hospital of Winterthur, Winterthur, Switzerland

Abstract

Purpose:

To identify OCT-based anatomical features and clinical characteristics for poor central retinal thickness (CRT) response to ranibizumab in neovascular age-related macular degeneration (AMD).

Patients and Methods:

Investigating our electronic patient records (Eyeswide), patients with neovascular AMD treated with intravitreal injections of 0.5mg/0.05ml ranibizumab were identified and their notes reviewed. Data collected included gender, age, initial best-corrected visual acuity (BCVA), prior photodynamic therapy, lesion type (classic versus occult), type of macular edema (intraretinal fluid, subretinal fluid, pigment epithelium detachment) and the total number of previous ranibizumab injections.

Results:

A total of 210 eyes of 182 patients with neovascular AMD were identified. Mean follow-up time was 1.34 years (SD ± 0.77). Central retinal thickness reduction in women was significantly inferior to that in men (p=0.05). Patients with cystoid type macular edema had significantly greater reduction in CRT compared to patients with subretinal fluid (p<0.001) or pigment epithelium detachment (p<0.001). The percentage drop of CRT was no longer statistically significant after the sixth injection. Age, initial BCVA, prior photodynamic therapy and lesion type had no statistically effect on CRT response.

Conclusion:

Risk factors for poor central retinal thickness response to ranibizumab include female gender and patients with predominant subretinal fluid or pigment epithelium detachment. Furthermore, the anatomical response decreased after the sixth injection of ranibizumab.

Keywords: Age-related macular degeneration, Lucentis, poor-responder, ranibizumab, risk factors.


Article Information


Identifiers and Pagination:

Year: 2014
Volume: 8
First Page: 3
Last Page: 6
Publisher Id: TOOPHTJ-8-3
DOI: 10.2174/1874364101408010003

Article History:

Received Date: 29/10/2013
Revision Received Date: 17/4/2014
Acceptance Date: 23/4/2014
Electronic publication date: 16 /5/2014
Collection year: 2014

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 1286
Abstract HTML Views: 768
PDF Downloads: 219
Total Views/Downloads: 2273

Unique Statistics:

Full-Text HTML Views: 503
Abstract HTML Views: 489
PDF Downloads: 130
Total Views/Downloads: 1122
Geographical View

© Guber et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Sutton Eye Hospital, Epsom and St Helier University Hospitals, NHS Trust, Cotswold Road, London, SM2 5NF, UK; Tel: +44 20 8296 2000; Fax: +44 20 8770 7051; E-mail: josef.guber@esth.nhs.uk§ Presented at the Annual Congress of the Royal College of Ophthalmologists, Liverpool, UK, May 2013.





BACKGROUND

Neovascular age-related macular degeneration (AMD) is a serious disorder of the central retina leading to rapid loss of central vision [1Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA 2004; 291: 900-1.-3Ferris FL3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984; 102: 1640-42.].

Ranibizumab (Lucentis®, Novartis Pharma AG, Switzerland), a humanized monoclonal antibody fragment targeting multiple isoforms of human vascular endothelial growth factor (VEGF), has revolutionized the treatment for neovascular AMD [4Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab. an anti-vascular endothelial growth factor antigen binding fragent.as therapy for neovascular age-related macular degeneration. Retina 2006; 26: 859-70.]. The efficacy and safety of ranibizumab have been demonstrated in major clinical trials [5Rosenfeld PJ, Brown DM, Heier JS , et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31.-8Schmidt-Erfurth U, Eldem B, Guymer R , et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE Study. Ophthalmology 2011; 118: 831-9.]. Ranibizumab’s therapeutic effect appears maximal within the first three months of treatment and regular treatment once a month is associated with optimum visual acuity and anatomical response [5Rosenfeld PJ, Brown DM, Heier JS , et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31., 6Brown DM, Kaiser PK, Michels M , et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432-44.]. However, the PrONTO Study showed that the visual outcome was similar using a variable-dosing regimen [9Lalwani GA, Rosenfeld PJ, Fung AE , et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009; 148(1): 43-58.].

Optical coherence tomography (OCT) is now regarded as the single most important tool in monitoring disease activity and treatment success. The decision for retreatment is generally based on OCT findings [10Fung AE, Lalwani GA, Rosenfeld PJ , et al. An optical coherence tomography-guided. variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143: 566-83.-12Holz FG, Amoaku W, Donate J , et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN Study. Ophthalmology 2011; 118: 663-71.].

The aim of the present study was to identify clinical characteristics at presentation for poor central retinal thickness response to intravitreal injections of ranibizumab in wet AMD.

PATIENTS AND METHODS

Patients

Research adhered to the tenets of the Declaration of Helsinki.

Investigating our electronic patient records (Eyeswide), patients with neovascular AMDtreated with intravitreal injections of 0.5mg/0.05ml ranibizumab were identified and their notes reviewed. The evidence of choroidal neovascularization (CNV) was confirmed by fluorescein angiography. Patients were treated with ranibizumab following the PrONTO regime [9Lalwani GA, Rosenfeld PJ, Fung AE , et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009; 148(1): 43-58.]. After a loading dose of three injections, criteria for further anti-VEGF injections were; detection of any intraretinal, subretinal fluid, serous pigment epithelium detachment, haemorrhage or drop in vision. Patients were followed up monthly and by OCT regardless whether they received an injection or not until six months after the last injection. The patient’s baseline characteristics are shown in Table 1.

Table 1

Patients characteristics at baseline.




Table 2

Multivariate analysis of predictive factors for central retinal thickness response to ranibizumab.




OCT scans (Cirrus™ HD-OCT 400, Software 4.0, Carl Zeiss Meditec, Jena, Germany) of these patients’ were reviewed by two trained observers. Macular edema was classified as either predominant intraretinal fluid (IRF), subretinal fluid (SRF) or as predominant pigment epithelium detachment (PED). In addition, intraretinal fluid was differentiated in cystoid type (cyst diameter > 150um) and spongiod type (cyst diameter < 150 um).

Statistics

To describe mean relative change in central retinal thickness (CRT) compared to a reference central retinal thickness (RCRT) for several predictors, a multivariate analysis was performed. Subject was treated as random factor. Results were presented as mean percentage differences to RCRT with the corresponding p-values and 95% confidence intervals. All evaluations were done using R version 15.1.

Reference central retinal thickness was defined for each eye as the mean foveal thickness of all examinations in which no intraretinal (IRF), subretinal fluid (SRF) or pigment epithelium detachment (PED) could be observed.

The factors analyzed were gender, age (50 to 74 versus ≥75 years), initial best corrected visual acuity (BCVA; LogMAR ≥0.4 versus 0.3 to 0.0), prior photodynamic therapy, lesion type (classic versus occult), type of macular edema and the total number of injections.

RESULTS

A total of 1141 injections in 210 eyes of 182 patients were performed. Mean number of injections per patient was 6 (range 2 - 14).Mean follow-up time was 1.34 years (range 0.16 - 3.39). Patients’ characteristics at baseline were summarized in Table 1.

The multivariate analysis of the various clinical factors showed that the central retinal thickness reduction in women was significantly inferior to that in men (-6.47%, 95%CI ± 6.56, p=0.05). Age, initial BCVA and prior photodynamic therapy had no effect on macular thickness response.

Statistical evaluation of the macular edema types revealed that patients with predominant intraretinal fluid (Δ to RCRT35.72%, 95%CI ± 10.8) responded better compared with patients with subretinal fluid (Δ to RCRT 28.97%, 95%CI ± 9.34, p=0.001) or pigment epithelium detachment (Δ to RCRT 27.61%, 95%CI ± 10.61, p=<0.001). Furthermore, subgroup analysis showed that patients with a cystoid type of macular edema (Δ to RCRT 44.26%, 95%CI ± 10.76) had a significantly greater reduction of macular thickness compared to patients with spongiod type of macular edema (Δ to RCRT 27.17%, 95%CI ± 10.86, p=0.001). Lesion type had no effect on macular thickness response. An overview of the multivariate analysis is summarized in Table 2.

Regarding the total number of injections: after the first injection maximum response is evident (Δ to RCRT 27.17%, 95%CI ± 10.86, p=0.001); thereafter the reduction of CRT remains stable until injection 6 (Δ to RCRT 18.42-12.16%, p<0.05). Further treatments did not lead to a statistically significant CRT reduction (Δ to RCRT <12%; Fig. 1).

Fig. (1)

Effect of ranibizumab on mean central retinal thickness in percentage by number of injection. The line marks the statistical significant response (p=0.05). RCRT = reference central retinal thickness.



DISCUSSION

Analysis of risk factors is of paramount importance for the understanding of a disease and has a high impact on our daily clinical practice. Furthermore, considering the significant treatment costs in patients with wet AMD, it is important to identify predictive factors in order to evaluate cost effectiveness.

We identified several baseline characteristics associated with the risk for poor reduction of macular edema including female gender, macular edema with predominant subretinal fluid and patients with a predominant pigment epithelium detachment. In addition, we found that the maximal reduction of CRT had occurred by injection six. Thereafter ranibizumab had no longer the same good effect on the central retinal thickness.

Different theories explain unrewarding therapeutic response to ranibizumab therapy. For instance, various reports describe resistance to anti-VEGF-A antibodies secondary to regulatory feedback loops: Schaal et al. introduced the concept of tachyphylaxis associated with repeated bevacizumab injections for neovascular AMD. They found that after approximately three injections of bevacizumab, the initial efficacy was decreased by 50% [13Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?. Ophthalmology 2008; 15(12): 2199-05.]. Another retrospective review found tachyphylaxis after five to ten injections of bevacizumab [14Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009; 29(6): 723-31.]. Similar to ANCHOR and MARINA studies, the response to treatment in our patient population was independent of baseline patient characteristics such as age, initial visual acuity and lesion type or prior photodynamic therapy [5Rosenfeld PJ, Brown DM, Heier JS , et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31., 6Brown DM, Kaiser PK, Michels M , et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432-44., 15Boyer DS, Antoszyk AN, Awh CC , et al. Subgroup analysis of the MARINA Study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007; 114: 246-52.].

These findings indicate that neovascular AMD may feature more subtle subgroups than previously known but further research is needed to correlate our findings with genetic genotype polymorphism which were recently described [16McKibbin M, Ali M, Bansal S , et al. CFH. VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Br J Ophthalmol 2012; 96(2): 208-12.]. However, we believe that our findings contribute to a better understanding of the prognosis of several subgroups in wet AMD and this should be taken in account and must be explained to the patient before treatment.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Andreas Schötzau, dipl. math., Department of Biomedicine, University Hospital Basel: statistical analysis.

Muhammad Usman Saeed, Consultant Ophthalmologist, Sutton Eye Hospital: review of the manuscript.

REFERENCES

[1] Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA 2004; 291: 900-1.
[2] Friedmann DS, O'Colmain BJ, Munoz B , et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564-72.
[3] Ferris FL3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984; 102: 1640-42.
[4] Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab. an anti-vascular endothelial growth factor antigen binding fragent.as therapy for neovascular age-related macular degeneration. Retina 2006; 26: 859-70.
[5] Rosenfeld PJ, Brown DM, Heier JS , et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31.
[6] Brown DM, Kaiser PK, Michels M , et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432-44.
[7] Regillo CD, Brown DM, Abraham P , et al. Randomized. double-maked.sham-controlled trial of ranibizumab for neovascular age-related macular degeneration PIER Study year 1. Am J Ophthalmol 2008; 145: 239-48.
[8] Schmidt-Erfurth U, Eldem B, Guymer R , et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE Study. Ophthalmology 2011; 118: 831-9.
[9] Lalwani GA, Rosenfeld PJ, Fung AE , et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009; 148(1): 43-58.
[10] Fung AE, Lalwani GA, Rosenfeld PJ , et al. An optical coherence tomography-guided. variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143: 566-83.
[11] Mitchell P, Korobelnik JF, Lanzetta P , et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 2010; 94(1): 2-13.
[12] Holz FG, Amoaku W, Donate J , et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN Study. Ophthalmology 2011; 118: 663-71.
[13] Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?. Ophthalmology 2008; 15(12): 2199-05.
[14] Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009; 29(6): 723-31.
[15] Boyer DS, Antoszyk AN, Awh CC , et al. Subgroup analysis of the MARINA Study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007; 114: 246-52.
[16] McKibbin M, Ali M, Bansal S , et al. CFH. VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Br J Ophthalmol 2012; 96(2): 208-12.

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents



Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open