HIGHLIGHTS
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Retinal fluid and vision outcomes were assessed in patients with neovascular age-related macular degeneration who were treated with ranibizumab.
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Vision gains were greater in eyes with residual vs resolved subretinal fluid.
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Vision gains were lower in eyes with residual vs resolved intraretinal fluid.
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Fluid–vision relationships are more complex than determining a wet or dry macula.
Graphical abstract
Purpose
To investigate the relationship between retinal fluid and vision in ranibizumab-treated patients with neovascular age-related macular degeneration (nAMD).
Design
Clinical cohort study using post hoc analysis of clinical trial data.
Methods
We assessed data from HARBOR (NCT00891735), a phase III, randomized, controlled trial. We reviewed 917 patients ≥50 years of age with subfoveal nAMD associated with subretinal (SRF) and/or intraretinal fluid (IRF) at baseline, screening, or week 1. The intervention was intravitreal ranibizumab 0.5 or 2.0 mg (all treatment arms pooled). Outcomes included mean best-corrected visual acuity (BCVA) and BCVA change from baseline at months (M) 12 and 24 evaluated by the presence/absence of SRF and/or IRF.
Results
Baseline BCVA was higher with residual vs resolved SRF at M12 (mean [95% confidence interval {CI}] 58.8 letters [57.2-60.4] vs 53.5 [52.4-54.5]) and M24 (59.3 letters [57.8-60.8] vs 53.5 [52.5-54.5]). Mean BCVA change (adjusted for baseline) to M12 was greater with residual vs resolved SRF (mean difference [95% CI], +2.4 letters [+0.1 to +4.7]), but lower with residual vs resolved IRF (−3.5 letters [−5.8 to −1.2]). Eyes with residual SRF (no IRF) exhibited the largest mean BCVA gains (M12, +14.1 letters; M24, +13.2 letters), followed by resolved SRF/IRF (M12, +10.6 letters; M24, +10.0 letters), residual SRF/IRF (M12, +7.2 letters; M24, +8.5 letters), and residual IRF only (M12, +5.5 letters; M24, +3.6 letters).
Conclusions
Vision outcomes (adjusted for baseline BCVA) through M24 were better in ranibizumab-treated eyes with residual vs resolved SRF, and worse with residual vs resolved IRF. Presence of residual retinal fluid requires a more complex and nuanced assessment and interpretation in the context of nAMD management.
Intravitreal anti–vascular endothelial growth factor (VEGF) injections are the first line of treatment for patients with neovascular age-related macular degeneration (nAMD). Although the rate of blindness caused by nAMD has been significantly reduced in the era of anti-VEGF therapy, , vision outcomes achieved in clinical practice have not matched those reported in clinical trials. The high burden associated with frequent injections and close monitoring poses a significant barrier to optimal treatment and contributes significantly to vision outcomes.
To reduce treatment burden and personalize anti-VEGF therapy according to patient need, treatment regimens have been developed based upon assessment of disease activity. One approach is a pro re nata (PRN; as-needed) treatment regimen, where a decision is made at each clinic visit (occurring at a fixed time interval) whether or not to administer an anti-VEGF injection based upon the anatomic and vision findings for the patient. Another tailored approach is the treat-and-extend regimen. In both of these approaches, patients generally initially receive ≥3 consecutive monthly treatments. With a treat-and-extend regimen, the time interval between follow-up visits can be shortened or lengthened (generally in 2-week increments) in relation to the presence or absence of disease activity, respectively. Identifying neovascular disease activity considers biomarkers of change in visual acuity, the presence or absence of new hemorrhages, and the presence or absence of subretinal fluid (SRF) and/or intraretinal fluid (IRF).
A key goal of both PRN and treat-and-extend regimens is to achieve and maintain a fluid-free retina despite increasing the intervals between anti-VEGF treatments. Indeed, SRF and IRF, detected using optical coherence tomography (OCT), are the 2 most frequent biomarkers of disease activity that are used to determine the interval between treatments. However, the assumed need to continue regular treatments to achieve a completely fluid-free retina is being debated, as well as whether it is imperative to continuously strive for complete resolution of fluid in cases when this is not being achieved with frequent treatments at close intervals.
Some data show that the relationship between residual retinal fluid and vision outcomes may not be straightforward. The FLUID trial found similar mean vision gains at month 24 in eyes treated with a ranibizumab 0.5 mg treat-and-extend regimen, which tolerated SRF ≤200 µm at the foveal center, after 3 monthly loading doses, compared with those treated and not extended until complete resolution of SRF was achieved (+3.0 vs +2.6 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). In this study, no active (ie, not deemed to be degenerative) IRF was tolerated in either treatment arm for interval extension. A post hoc analysis of the CATT trial found that presence of residual SRF at month 24 was associated with better visual acuity after 2 years of treatment with ranibizumab or bevacizumab. Conversely, the presence of residual IRF was independently associated with worse vision at year 2. The presence of IRF at baseline has also been associated with a higher risk of macular atrophy over 24 months of ranibizumab treatment, whereas baseline SRF was associated with a lower risk of macular atrophy. Our assumptions about the need to return the retina to a completely dry state and the interpretation of OCT fluid-filled spaces as a biomarker of disease activity need further exploration as we try to better understand the nAMD disease state to elucidate the appropriate treatment goals with respect to retinal fluid when managing nAMD with anti-VEGF therapy.
This post hoc analysis of the HARBOR trial examined the association of retinal fluid with best-corrected visual acuity (BCVA) outcomes in patients with baseline retinal fluid who were receiving ranibizumab for treatment-naïve nAMD. Specifically, this study investigated BCVA outcomes evaluated by the presence (residual) or absence (resolved) of SRF and/or IRF in eyes with ranibizumab treatment and follow-up over 24 months.
METHODS
STUDY DESIGN
The full methods for the HARBOR trial have been published previously. Briefly, the HARBOR trial was a 24-month, phase III, randomized, multicenter, double-masked, active treatment–controlled study (ClinicalTrials.gov identifier NCT00891735) conducted at 100 sites in the United States. The HARBOR trial was conducted in accordance with Good Clinical Practice (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E6), applicable US Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act. Institutional review boards approved the protocol before the start of the study and all patients provided written informed consent before enrollment that extended to the use of individual patient data for further analyses.
The HARBOR trial randomized 1097 treatment-naïve patients with subfoveal nAMD. Patient eligibility was determined by a reading center using fundus photographs and fluorescein angiography. Patients were randomized to receive intravitreal ranibizumab 0.5 mg or 2.0 mg, administered either monthly or PRN, after 3 loading doses. All patients attended monthly monitoring visits, and those randomized to the PRN arms received retreatment if they displayed a ≥5-letter decrease in BCVA from the previous visit or any evidence of disease activity on OCT, as indicated by any SRF, IRF, or pigment epithelial detachment.
POST HOC ANALYSES
The current study included HARBOR study eyes with 24 months of available OCT data and evidence of SRF and/or IRF at the screening, baseline, or week 1 visits (N = 917, all treatment arms pooled); for the remainder of this report, we will refer to screening, baseline, or week 1 as simply “baseline.” The presence of retinal fluid over 24 months was assessed using OCT b-scans at each visit, which were independently graded for SRF or IRF by masked graders in a post hoc OCT image analysis performed at the Doheny Image Reading and Research Lab.
The presence of SRF and IRF was assessed by reviewing all b-scans in the spectral-domain OCT volume. Scan evaluations were completed by 2 masked graders at the Doheny Image Reading and Research Lab (an additional grader was available to adjudicate any discrepancies). SRF was defined as evidence of a hyporeflective cavity occurring between the photoreceptor layer and the retinal pigment epithelium (RPE), and IRF was defined by hyporeflective cystoid intraretinal space separated by thin reflective septa. For these analyses, subretinal pigment epithelium (sub-RPE) fluid was not evaluated. There was no tolerance of any fluid in these definitions.
Outcomes of these analyses included the proportion of eyes with SRF and IRF at baseline as well as with residual or resolved SRF and IRF at months 12 and 24. In addition, mean BCVA was assessed for patients with residual SRF or IRF at months 12 and 24. Baseline BCVA was compared in eyes that had residual or resolved SRF or IRF at months 12 and 24 to understand whether those groups had any differences before receiving treatment that may have impacted BCVA. Observed BCVA and BCVA gains (adjusted for baseline BCVA) at months 12 and 24 were evaluated by concurrent SRF and/or IRF presence or absence. Additional outcomes included the proportion of eyes with Snellen equivalent of 20/40 or better vision (≥69 ETDRS letters) at months 12 and 24, evaluated by baseline and concurrent SRF and/or IRF presence or absence.
However, an eye with residual SRF may also have had residual IRF. Thus, as an additional evaluation of the potential impact of the specific types of retinal fluid, either alone or together, on BCVA outcomes, an overall analysis of observed BCVA (ETDRS letters) and change from baseline BCVA was performed. In this analysis, patients were grouped not only according to presence or absence of SRF or IRF, but also to whether they had SRF or IRF alone or simultaneously at month 12 or 24. Group 1 (residual SRF only) included patients with SRF but not IRF at the same time points. Group 2 (residual IRF only) included patients with IRF but not SRF at the same time points. Group 3 (residual SRF and IRF) included patients with both SRF and IRF at the same time points. Group 4 (dry retina) included all retinal fluid resolved at the same time points.
STATISTICAL ANALYSIS
These post hoc analyses used observed data, with no imputation for missing values. Because observed data were used, the total patients (denominators) for each group may not all reflect the total sample of 917 eyes. Because of an imbalance in baseline BCVA between eyes with residual and resolved SRF at months 12 and/or 24, all change from baseline BCVA measures were adjusted for baseline BCVA using an analysis of covariance model. Logistic regression models were used to estimate the odds and 95% confidence intervals (CIs) of having 20/40 or better vision at months 12 and 24 by the presence of SRF and/or IRF at each time point, and these models controlled for baseline BCVA. Statistical analyses were performed using SAS software (version 9.4; SAS Institute Inc., Cary, North Carolina, USA).
RESULTS
BASELINE CHARACTERISTICS
The present analysis of the HARBOR trial included 917 ranibizumab-treated eyes with OCT evidence of SRF and/or IRF at baseline. At baseline, 85.6% (785/917) and 63.1% (577/914) of eyes exhibited SRF and IRF, respectively (not mutually exclusive; Figure 1 ). Mean baseline BCVA was 54.6 letters (95% CI 53.7-55.5), or Snellen equivalent of 20/80, for eyes with SRF, and 52.4 letters (95% CI 51.3-53.4), or Snellen equivalent of 20/100, for eyes with IRF.
When baseline characteristics were evaluated by various scenarios of fluid status, 36.9% (337/914), 14.4% (132/914), and 48.7% (445/914) showed SRF only, IRF only, and a combination of SRF and IRF, respectively. The mean (95% CI) baseline BCVA for these groups were 58.2 (57.0-59.4), 53.7 (51.6-55.9), and 52.0 (50.8-53.1) letters for eyes with SRF only, IRF only, and SRF and IRF, respectively; these BCVA letters correspond to Snellen equivalents of 20/80, 20/80, and 20/100, respectively.
BCVA OUTCOMES IN EYES EVALUATED BY FLUID TYPE AT BASELINE AND RESIDUAL OR RESOLVED FLUID AT THE MONTH 12 AND 24
The goal of the HARBOR trial was treatment to a dry state; however, approximately one-fifth of eyes with retinal fluid (SRF and/or IRF) at baseline showed residual SRF at months 12 (19.5%, 174/892) and 24 (18.2%, 163/896; Figure 1 ). In addition, a little more than one-fourth of eyes with retinal fluid at baseline showed evidence of IRF after 12 and 24 months of ranibizumab treatment (27.7% [248/894] and 27.5% [247/899], respectively).
Baseline BCVA was assessed for the groups of residual or resolved SRF or IRF at months 12 and 24. Baseline BCVA was higher in eyes with residual SRF (mean [95% CI], 58.8 letters [57.2-60.4], or Snellen equivalent of 20/62.5) compared with those with resolved SRF at month 12 (53.5 letters [52.4-54.5], or Snellen equivalent of 20/80). Similarly, at month 24, eyes with residual SRF had greater baseline BCVA (59.3 letters [57.8-60.8], or Snellen equivalent of 20/62.5) than eyes with resolved SRF (53.5 letters [52.5-54.5], or Snellen equivalent of 20/80).
Because of the imbalances in baseline BCVA described above, changes in BCVA measures were adjusted for baseline BCVA. Adjusted mean change in BCVA from baseline at month 12 was greater in eyes with residual (mean [95% CI], +11.9 letters [9.9-14.0]) vs resolved SRF (+9.5 letters [8.4-10.6]), with a difference of +2.4 letters (0.1-4.7). At month 24, change in BCVA from baseline was also greater in eyes with residual (+11.7 letters [9.2-14.1]) vs resolved SRF (+8.6 letters [7.4-9.8]), with a difference of +3.1 letters (+0.3 to +5.8; Figure 2 , A).
