Author reply

Abstract

We thank Matonti et al for their interest in our study (SECURE). Matonti et al mention in their letter that the mean BCVA decrease of 4.3 letters from baseline observed in the SECURE study may be owing to retinal nerve fiber layer (RNFL) decrease and intraocular pressure (IOP) increase secondary to intravitreal injections of ranibizumab. The hypothetical link between RNFL and changes in BCVA cannot be substantiated based on the SECURE study, because RNFL was not assessed in the SECURE study or in its prestudies, EXCITE and SUSTAIN. Martinez de la Casa et al1Martinez-de-la-Casa J.M. Ruiz-Calvo A. Saenz-Frances F. et al.Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab.Invest Ophthalmol Vis Sci. 2012; 53: 6214-6218Crossref PubMed Scopus (78) Google Scholar recently described thinning of RNFL after ranibizumab treatment. However, this 12-month, longitudinal study included a relatively small patient population (N = 49) and their finding warrants confirmation by larger, randomized, controlled trials.As mentioned by Matonti et al, IOP spikes after intravitreal injection of any drug, including ranibizumab, are typically observed within the first 15–30 minutes of the injection, and are usually transient. Sustained IOP increase related to repeated intravitreal injections has been reported by Tseng et al,2Tseng J.J. Vance S.K. Della Torre K.E. et al.Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration.J Glaucoma. 2012; 21: 241-247Crossref PubMed Scopus (107) Google Scholar but the limited sample size (N = 23) in their report does not allow for generalization of this observation. In SECURE, an adverse event of transient IOP increase was reported for 15 patients (6.4%). At study end, these 15 patients had no greater loss in BCVA compared with the overall patient population (−3.5 vs −4.5 letters for overall population). All postinjection IOP elevations were reported to be transient with no optic nerve damage or newly diagnosed glaucoma reported in our study. The hypothesis of Matonti et al that BCVA decrease may have been influenced by IOP increase is thus not supported by data from the SECURE study.The observed average BCVA decrease over time in SECURE is more likely owing to undertreatment of patients or as factors other than loss of visual acuity (VA) were considered for the retreatment decision by the investigator. This interpretation is based on the fact that 41.9% of the patients had ≥7 visits at which ranibizumab was not administered, although they had a VA loss of >5 letters. That undertreatment is one of the major factors contributing to VA decline is supported by several large, 2-year studies such as MARINA, ANCHOR,3LUCENTIS [ranibizumab injection] Full prescribing information USA. February 2013.Google Scholar and the more recent CATT4Martin D.F. Maguire M.G. Fine S.L. et al.Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Abstract Full Text Full Text PDF PubMed Scopus (1395) Google Scholar study, which used a greater number of ranibizumab injections demonstrating more favorable VA outcomes than what has been observed in SECURE (mean of 6.1 injections over 2 years). Additionally, over 2 years, 24% of the patients in both ANCHOR and MARINA studies reported IOP increased as an adverse event and despite this, had favorable VA outcomes.3LUCENTIS [ranibizumab injection] Full prescribing information USA. February 2013.Google ScholarMoreover, during the natural progression of neovascular age-related macular degeneration, 40% of the patients may experience severe vision loss (>6 lines compared with baseline) within 3 years of diagnosis5Wong T.Y. Chakravarthy U. Klein R. et al.The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis.Ophthalmology. 2008; 115: 116-126Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar showing that the mean VA change in SECURE (-4.3 hanging letters) over 2 years is a positive response to ranibizumab treatment, albeit not as extensive as seen in studies with a greater frequency of dosing.We agree with the authors that important sequelae of any type of potential adverse events such as increased IOP need to be addressed and monitored carefully by adequate and efficient pharmacovigilance programs and research to address any potentially harmful effects by anti-vascular endothelial growth factor (VEGF) agents. However, we believe that the SECURE study data does not support the hypothesis by Matonti et al that RNFL decrease or transient or chronic increase in IOP following intravitreal injection of anti-VEGF agents contributes to visual loss owing to blockage of the neurotrophic pathway of VEGF. We thank Matonti et al for their interest in our study (SECURE). Matonti et al mention in their letter that the mean BCVA decrease of 4.3 letters from baseline observed in the SECURE study may be owing to retinal nerve fiber layer (RNFL) decrease and intraocular pressure (IOP) increase secondary to intravitreal injections of ranibizumab. The hypothetical link between RNFL and changes in BCVA cannot be substantiated based on the SECURE study, because RNFL was not assessed in the SECURE study or in its prestudies, EXCITE and SUSTAIN. Martinez de la Casa et al1Martinez-de-la-Casa J.M. Ruiz-Calvo A. Saenz-Frances F. et al.Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab.Invest Ophthalmol Vis Sci. 2012; 53: 6214-6218Crossref PubMed Scopus (78) Google Scholar recently described thinning of RNFL after ranibizumab treatment. However, this 12-month, longitudinal study included a relatively small patient population (N = 49) and their finding warrants confirmation by larger, randomized, controlled trials. As mentioned by Matonti et al, IOP spikes after intravitreal injection of any drug, including ranibizumab, are typically observed within the first 15–30 minutes of the injection, and are usually transient. Sustained IOP increase related to repeated intravitreal injections has been reported by Tseng et al,2Tseng J.J. Vance S.K. Della Torre K.E. et al.Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration.J Glaucoma. 2012; 21: 241-247Crossref PubMed Scopus (107) Google Scholar but the limited sample size (N = 23) in their report does not allow for generalization of this observation. In SECURE, an adverse event of transient IOP increase was reported for 15 patients (6.4%). At study end, these 15 patients had no greater loss in BCVA compared with the overall patient population (−3.5 vs −4.5 letters for overall population). All postinjection IOP elevations were reported to be transient with no optic nerve damage or newly diagnosed glaucoma reported in our study. The hypothesis of Matonti et al that BCVA decrease may have been influenced by IOP increase is thus not supported by data from the SECURE study. The observed average BCVA decrease over time in SECURE is more likely owing to undertreatment of patients or as factors other than loss of visual acuity (VA) were considered for the retreatment decision by the investigator. This interpretation is based on the fact that 41.9% of the patients had ≥7 visits at which ranibizumab was not administered, although they had a VA loss of >5 letters. That undertreatment is one of the major factors contributing to VA decline is supported by several large, 2-year studies such as MARINA, ANCHOR,3LUCENTIS [ranibizumab injection] Full prescribing information USA. February 2013.Google Scholar and the more recent CATT4Martin D.F. Maguire M.G. Fine S.L. et al.Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Abstract Full Text Full Text PDF PubMed Scopus (1395) Google Scholar study, which used a greater number of ranibizumab injections demonstrating more favorable VA outcomes than what has been observed in SECURE (mean of 6.1 injections over 2 years). Additionally, over 2 years, 24% of the patients in both ANCHOR and MARINA studies reported IOP increased as an adverse event and despite this, had favorable VA outcomes.3LUCENTIS [ranibizumab injection] Full prescribing information USA. February 2013.Google Scholar Moreover, during the natural progression of neovascular age-related macular degeneration, 40% of the patients may experience severe vision loss (>6 lines compared with baseline) within 3 years of diagnosis5Wong T.Y. Chakravarthy U. Klein R. et al.The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis.Ophthalmology. 2008; 115: 116-126Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar showing that the mean VA change in SECURE (-4.3 hanging letters) over 2 years is a positive response to ranibizumab treatment, albeit not as extensive as seen in studies with a greater frequency of dosing. We agree with the authors that important sequelae of any type of potential adverse events such as increased IOP need to be addressed and monitored carefully by adequate and efficient pharmacovigilance programs and research to address any potentially harmful effects by anti-vascular endothelial growth factor (VEGF) agents. However, we believe that the SECURE study data does not support the hypothesis by Matonti et al that RNFL decrease or transient or chronic increase in IOP following intravitreal injection of anti-VEGF agents contributes to visual loss owing to blockage of the neurotrophic pathway of VEGF. Long-term Safety of Ranibizumab in Neovascular Age-related Macular DegenerationOphthalmologyVol. 120Issue 9PreviewWe read with interest the study from Silva et al1 on the long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration (nAMD). It described visual outcomes, drug tolerability, and safety of ranibizumab (Lucentis; Novartis Pharma AG, Basel, Switzerland, and Genentech, Inc, South San Francisco, CA) over a 24-month follow-up in selected patients with nAMD previously treated for 1 year in other studies on ranibizumab. The authors concluded that ranibizumab administered as per a visual acuity-guided flexible dosing regimen was well tolerated, and observed that on average, mean best-corrected visual acuity declined by 4.3 letters from the baseline. Full-Text PDF