Management of neovascular age-related macular degeneration with ranibizumab: Long-term outcomes and second eye outcomes

Abstract

Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are the established standard of care for neovascular age related macular degeneration (nAMD), however there are currently limited data on long-term outcomes of this therapy. Ranibizumab is one such anti-VEGF agent administered to treat nAMD. Patients diagnosed with nAMD undergo regular clinic based follow-up as part of their treatment, often on a monthly basis. Assessment during these appointments includes optical coherence tomography (OCT) scans, which can contribute to the detection of nAMD in the second eye. There is limited data on the symptomatic status, clinical presentation and outcomes of second eye nAMD whilst undergoing regular assessment for the first treatment eye under these conditions. Aims: The first aim of this thesis is to evaluate the long-term (5-year) outcomes of intravitreal ranibizumab (an anti-VEGF agent) in treating nAMD by examining a cohort within a real life clinic setting. The second aim is to compare the clinical presentation and treatment outcomes between the first and second treated eyes in patients that developed nAMD in both eyes, whilst under regular review for unilateral nAMD. Methods: A total of 208 patients (208 eyes) were included in a retrospective case series assessing the 5-year outcomes of nAMD treated with ranibizumab, entitled the long-term ranibizumab study (LTRS) (Chapter 3). Intervention was an individualised treatment model after three initial monthly loading doses. Visual acuity (VA), central macular thickness (CMT), qualitative OCT features, and adverse events (AE) were determined for each visit. Snellen VA was converted to Early Treatment Diabetic Retinopathy Study (ETDRS) letters for analysis. To assess outcomes of second eyes diagnosed with nAMD, a retrospective case series entitled second-eye ranibizumab study (SERS) forms the second part of this thesis (Chapter 4). Forty-five consecutive patients fulfilled the inclusion criteria of commencing treatment with ranibizumab in the first eye for nAMD between July 2007 and March 2011,and subsequently developing nAMD in the second eye with at least 12-months of follow-up in each eye. Treatment was administered under the same conditions as the LTRS. Snellen VA was measured, and OCT examination of both eyes at each visit assessed the presence of intra-retinal fluid (IRF) and sub-retinal fluid (SRF). Patient reported symptoms were recorded at every clinic visit. Paired t-tests were used to assess changes in VA and CMT over the study duration of the LTRS and SERS and two sample t- tests were used to evaluate VA differences between groups. Changes in VA compared to baseline were classified into the three categories: stable VA (loss or gain of ≤15 letters), improved VA (gain of >15 letters), or worse VA (loss of >15 letters). Linear regression was used to assess the effects of age, gender, number of injections, previous treatment, medical history, medications, and baseline VA on both VA and CMT changes. Chi-square test or Fisher’s exact test were used to measure proportions of patients with visual stability and OCT fluid free status at 12-months in the SERS. Results: In the LTRS, mean VA improved by 1.9 letters after 1 year (p=0.020) and decreased by 2.4 letters over 5-years of the treatment (p=0.040). At the end of year 5, 11.1% (23/208) of patients improved VA by more than 15 letters and 68.8% (143/208) of patients had stable VA, while 20.2% (42/208) patients lost more than 15 letters. Patients with VA less than 35 letters (approximate Snellen VA 6/60) at baseline showed significant VA improvement after 5-years of treatment (mean increase 11.5 letters, p=0.01), whilst those that were between 70 and 85 letters (approximate Snellen VA 6/12 to 6/6) at baseline showed a mean decrease (-12.9 letters, p=<0.001). There was a positive relationship between injection numbers and VA improvement over the 5-years after adjusting for age and baseline VA (Regression coefficient 0.3, P<0.001). Mean CMT decreased by 28.3μm (p<0.01) over 5-years. Ocular AE, ocular serious adverse events (SAE) and systemic SAE occurred in 4.6%, 0.48% and 2%, respectively, during the follow-up period. Thirty-six per cent of patients did not require an injection in their 5th year of follow-up, whilst 24% of patients required near monthly (10-12) injections in the 5th year. In the SERS, second treated eyes commencing treatment with good VA at baseline (defined as >76 letters, or Snellen VA approximately 6/9)) showed greater stability of vision at 12-months vs. first treated eyes (p=0.05). There was no significant difference in mean VA change between first and second treated eyes. The proportion of OCT - fluid free eyes was higher amongst second treated eyes compared with first treated eyes at 12-months (70% vs. 40%, p=0.02). Intra-retinal fluid (IRF) was seen in 54% of second treated eyes at baseline compared with 84% in first treated eyes (p=0.01). Symptoms were absent in 54% of second treated eyes at baseline. The most common symptoms were “blurred vision” (28% of all patients) and metamorphopsia (11% of all patients). Conclusions: The visual gains achieved were not as significant as clinical trials, likely reflecting the differences in inclusion criteria of patients, and less rigorous follow-up and treatment. Intravitreal ranibizumab was effective in maintaining vision in patients with nAMD and reducing macula thickness over 5-years using an individualised treatment regime in a real-world setting.. Ranibizumab is a safe drug to use over 5-years in a real-world clinical setting. In patients undergoing treatment for nAMD in the first eye, OCT screening of the second eye at each visit may be necessary to detect second eye nAMD in this at-risk population. A large proportion of patients are asymptomatic at diagnosis of second eye disease, and a significant proportion of patients were detected to have treatable subfoveal nAMD with OCT alone. Second eye disease detected and treated by such a protocol showed a lower rate of IRF at baseline, suggesting early detection had occurred. Second eyes showed a higher rate of fluid free status at 12-months compared to the first treated eye, suggesting that early detection and treatment led to improved anatomical outcomes, potentially explaining superior VA outcomes. Patients commencing treatment in their second eye with good VA had better visual outcomes compared to those with worse VA.