Efficacy and safety of intravitreal aflibercept in ranibizumab-refractory patients with neovascular age-related macular degeneration

Abstract

Background: Anti-vascular endothelial growth factor (anti-VEGF) agents have become the standard of care in neovascular age-related macular degeneration (nAMD). Despite generally excellent response rates to anti-VEGF therapy, some patients do not respond or may respond suboptimally. In the case of refractory or rapidly recurring fluid in nAMD, clinicians may switch to another anti-VEGF agent. TITAN was an observational study that assessed the effectiveness and safety of intravitreal aflibercept (IVT-AFL) in patients with nAMD refractory to ranibizumab who switched to IVT-AFL after less than 12 months of ranibizumab treatment in routine clinical practice in France.

Methods: TITAN was an observational, retrospective and prospective 12-month study conducted at 28 centres in France. Patients with nAMD refractory to ranibizumab were enrolled. Patients who were switched from ranibizumab to IVT-AFL were followed for 12 months. Data were obtained from medical records for retrospectively included patients, and at routine follow-up visits for those included prospectively. The main outcome measure was percentage of patients who achieved treatment success (gain of ≥1 Early Treatment Diabetic Retinopathy Study letters in best-corrected visual acuity [BCVA] and/or any reduction in central retinal thickness [CRT]) from baseline to 12 months after switching. A sample size of 225 patients was determined based on a 2-sided 95% confidence interval with a width equal to 0.12 when the sample proportion was 0.70.

Results: We analysed safety data (N = 217) and clinical outcomes from patients in the per-protocol population (n = 125). The mean (standard deviation) number of IVT-AFL injections was 7.5 (2.6). Treatment success was achieved in 68.8% of patients. Mean BCVA change from baseline to Month 12 was + 1.5 letters (P = 0.105) and the mean CRT change was - 45.0 μm (P < 0.001). In a subgroup analysis, in patients who received three initial monthly IVT-AFL injections, mean BCVA gain was 3.3 letters at Month 12 (P = 0.015). Excluding lack of efficacy and inappropriate scheduling of drug administration, the most common adverse event was eye pain (2.3%).

Conclusions: Switching ranibizumab-refractory patients with nAMD to IVT-AFL may improve visual outcomes in some patients, particularly those who receive three initial monthly injections.

Trial registration: ClinicalTrials.gov , NCT02321241 . First posted: December 22, 2014; Last update posted: July 2, 2018.

Keywords: Age-related macular degeneration; Exudative; Observational; Retina; Switch.

Conflict of interest statement

SR: Consulting fees from Allergan, Bayer and Novartis; LK: Financial support from Novartis, Allergan, Bayer, Thea and Alcon; consulting fees from Alcon, Alimera, Allergan, Bayer, Roche and Novartis; research funding from Alcon, Alimera, Allergan, Bayer, Horus, Novartis and Thea Pharmaceuticals; AGA: Consulting fees from Alimera, Allergan, Bayer and Novartis; ID: Employee of Bayer HealthCare SAS; ES: Consulting fees and financial support from Allergan, Bayer, Novartis, Roche and Thea Pharmaceuticals.

Figures

Fig. 1

Patient disposition. *Three initial monthly injections (− 1/+ 2 weeks). The per-protocol population was defined as patients without protocol deviation and with BCVA/CRT assessments prior to any treatment (ranibizumab) at baseline and at Month 12 (n = 125). The FAS included patients who received ≥1 IVT-AFL treatment and had BCVA and CRT assessments in the study eye at baseline and during follow-up (n = 185). BCVA = best-corrected visual acuity; CRT = central retinal thickness; FAS = full analysis set; IVT-AFL = intravitreal aflibercept; SAS = safety analysis set

Fig. 2

Proportion of patients with SRF, IRF and sub-RPE. At baseline (prior to switch) (a) and at Month 12 (following switch) (b). IRF = intraretinal fluid; SRF = subretinal fluid; sub-RPE = sub-retinal pigment epithelium. Any treatment includes ranibizumab. *Twelve patients without SRF at baseline were found with SRF at least once over the follow-up and three of them switched from IVT-AFL to ranibizumab. †Twenty-three patients without IRF at baseline were found with IRF at least once over the follow-up and one of them switched from IVT-AFL to ranibizumab. ‡Thirteen patients without sub-RPE fluid at baseline were found with sub-RPE fluid at least once over the follow-up and two of them switched from IVT-AFL to ranibizumab

Fig. 3

Distribution of number of intravitreal aflibercept injections over the 12-month study. Per-protocol population. IVT-AFL = intravitreal aflibercept

Fig. 4

Distribution of patients by absolute final BCVA subgroups (n = 125. Per-protocol population. BCVA = best–corrected visual acuity