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Clinical science
Intraretinal cysts are the most relevant prognostic biomarker in neovascular age-related macular degeneration independent of the therapeutic strategy
  1. Markus Ritter1,
  2. Christian Simader1,
  3. Matthias Bolz1,
  4. Gábor G Deák1,
  5. Ulrike Mayr-Sponer1,
  6. Ramzi Sayegh1,
  7. Michael Kundi2,
  8. Ursula M Schmidt-Erfurth1
  1. 1Department of Ophthalmology, Medical University of Vienna, Vienna, Austria
  2. 2Center for Public Health, Institute of Environmental Health, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Dr Christian Simader, Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; christian.simader{at}meduniwien.ac.at

Abstract

Background/aims To investigate the impact of antiangiogenic monotherapy and photodynamic therapy (PDT) as add-on strategy on retinal morphology, and to analyse prognostic biomarkers for visual outcome and retreatment frequency in neovascular age-related macular degeneration (nAMD).

Methods 255 patients participating in the MONT BLANC study were evaluated. Patients were randomised to receive as-needed ranibizumab monotherapy or combination therapy (verteporfin PDT and ranibizumab). Outcome measures included visual acuity (VA), retinal morphology assessed by optical coherence tomography and retreatment frequency.

Results The proportion of scans showing intraretinal cysts (IRC) or subretinal fluid (SRF) decreased more intensively in the combination than in the monotherapy group. Pigment epithelial detachments (PED) decreased significantly only in the combination group. Patients with IRC presented the lowest initial VA, and IRC had the strongest negative predictive value for functional improvement in both groups. SRF showed a predictive value for a higher number of ranibizumab injections (combination, +0.9; monotherapy, +0.8) and a higher number of PDT treatments in the combination group (+0.3). PED was associated with a higher number of ranibizumab injections only in the monotherapy group (+1.2).

Conclusions Combination and monotherapy showed a distinct response pattern for morphological parameters in nAMD. IRC was the only relevant prognostic parameter for functional outcome.

Trial registration number NCT00433017.

  • Imaging
  • Macula
  • Neovascularisation
  • Treatment Medical
  • Degeneration

https://doi.org/10.1136/bjophthalmol-2014-305186

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    Introduction

    Treatment of neovascular age-related macular degeneration (nAMD) has derived substantial benefit from advancement in retinal imaging using optical coherence tomography (OCT) in the era of anti-vascular endothelial growth factor (VEGF) therapies. The identification of VEGF-A as a key factor in the pathogenesis nAMD1 resulted in the development of ranibizumab, a monoclonal antibody that inhibits multiple isoforms of VEGF-A.2 Large clinical trials have demonstrated safety and efficacy of different dosing regimens in improving best-corrected visual acuity (BCVA) in patients with nAMD.3 ,4

    The other approved therapeutic strategy in choroidal neovascular (CNV) disease is verteporfin photodynamic therapy (PDT) which is effective in stabilising vision in patients by selectively occluding the CNV lesion while preserving the neurosensory retina.5

    Since ranibizumab and verteporfin PDT act on diverse pathophysiologic mechanisms of nAMD, it was suggested that a combination of both treatments may be synergistic, leading to fewer retreatments and increased durability of the benefit. The MONT BLANC and the DENALI studies investigated the efficacy and safety of verteporfin PDT in combination with ranibizumab, in comparison with ranibizumab monotherapy over 12 months.6 ,7 In the MONT BLANC study, the combination of a pro re nata (PRN) regimen with verteporfin PDT and ranibizumab was effective in improving BCVA comparable with ranibizumab monotherapy but ineffective with respect to reducing the number of ranibizumab retreatments during the 12-month study period.6

    The relevance of different OCT-derived parameters as prognostic and retreatment criteria during management of nAMD is vastly controversial. Since it has been shown that even accurate measurements of retinal thickness may fail to correlate with visual function or even predict visual outcomes,8 ,9 recent clinical imaging research has focused on the identification of clinically relevant OCT-based parameters in retinal morphology.10–12 Several studies investigated the fluid-related changes of individual retinal compartments after anti-VEGF therapy,11–14 verteporfin PDT13 ,15–17 and combination treatment.18 ,19

    The aim of the present study was to identify relevant prognostic biomarkers in OCT morphology and to delineate therapy-specific biological response patterns of retinal and subretinal compartments in a prospective, randomised, clinical trial using a PRN regimen with monotherapy versus combination therapy.

    Materials and methods

    Study design and therapeutic procedures

    MONT BLANC was a multicenter, double-masked, randomised, active-controlled, phase II study assessing the efficacy and safety of a combination of verteporfin PDT and ranibizumab for treatment of subfoveal CNV secondary to AMD.6

    Patients were randomised to either the as-needed (PRN) combination treatment regimen (verteporfin PDT 6 mg/m2 and ranibizumab 0.5 mg) (arm 1) or the PRN ranibizumab monotherapy (sham infusion (5% dextrose) PDT and ranibizumab 0.5 mg) arm (arm 2).

    One study eye was selected in each patient. Details regarding the treatment schedule, VA assessment, study sites, inclusion and exclusion criteria, and safety assessment of the study are described elsewhere.6

    Morphological analysis using OCT

    The Vienna Reading Center (VRC), an independent, masked, central reading centre evaluated OCT images to provide a uniform assessment of retinal morphology for each monthly assessment of all participants. Stratus-OCT (Carl Zeiss Meditec, Dublin, California, USA) scans were acquired by certified operators at each study site using the fast macular thickness map scan mode for measurement of the central retinal thickness (CRT) and a 6 mm cross-hair scan mode for qualitative assessment of retinal morphology. Validated computer-assisted grading software was used at the VRC. This software imports OCT scan data from the Stratus-OCT and allows the reader to grade various parameters only in the 6 mm cross-hair scans following a defined algorithm.20 The readers were trained and certified according to the individual protocol of the VRC.

    OCT scans were graded for presence of intraretinal cysts (IRC), subretinal fluid (SRF) and pigment epithelial detachment (PED). Definition of morphological parameters was described previously.20

    Statistical analysis

    Partial correlation coefficients between δ BCVA (difference to baseline) and δ CRT were calculated holding constant the influence of morphologic changes (IRC, SRF and PED). BCVA was analysed by generalised estimation equations with an unstructured covariance matrix and normal deviates. Influence of morphology on BCVA was analysed by adding morphology status at baseline to this model. Frequency of IRC, SRF and PED were analysed using a logistic link function. For analysis of predictive values of morphology on visual function, a cut-off of +5 letters at month 12 was used. A p value of ≤0.05 was considered statistically significant.

    Results

    Patients

    Of the 255 patients included in the combination (n=122) and monotherapy (n=133) groups, 240 patients (94%) completed 12 months. The patients’ disposition, baseline and ocular disease characteristics, treatment exposure, as well as BCVA and CRT time course in the two treatment arms are described in detail elsewhere.6

    Specific response of different morphological parameters

    Intraretinal cysts

    Morphologic grading at baseline revealed IRC in 69 (53%) patients in the monotherapy and in 60 (49%) patients in the combination group. A highly significant (p<0.001) reduction of scans presenting with IRC during the loading phase (the first three consecutive, monthly injections) could be identified in both treatment groups (figure 1A).

    Figure 1
    Figure 1

    Comparison of the response of intraretinal cysts (IRC) (A), subretinal fluid (SRF) (B) and pigment epithelial detachment (PED) (C) to treatment in the combination and the monotherapy group during follow-up. Significant differences are indicated by a star (*) (p<0.05).

    IRC reached lowest values at month 3 in both treatment groups, thereafter, a moderate reincrease in the rate of IRC was observed in both groups during the maintenance phase. The number of patients presenting with IRC at baseline was reduced by 75% at month 3 in the combination group and by 67% in the monotherapy group (p=0.094). The difference reached statistical significance at months 2, 4, 5, 8 and 10.

    Subretinal fluid

    At baseline, 75 (58%) patients in the monotherapy and 82 (67%) patients in the combination group showed SRF. Both treatment groups showed a rapid resolution of SRF during the loading phase (figure 1B). However, at month 3, the number of scans showing persistence of SRF was significantly higher in the monotherapy group when compared with the combination group (p=0.022) despite the lower proportion of SRF at baseline. Resolution of SRF also required a longer time interval in the monotherapy group (p=0.076). In both treatment groups, the initial decrease was followed by maintenance of the improved values thereafter. However, the difference between the two groups was not maintained at month 12.

    Pigment epithelial detachment

    Eighty-one (62%) patients in the monotherapy and 74 (61%) patients in the combination group presented with PED before treatment initiation.

    Only the combination therapy showed a significant (p=0.012) positive response to therapy during the loading phase (figure 1C). The resolution of PED was significantly more pronounced in the combination therapy group when compared with the monotherapy group (p=0.022). This difference was greatest after the loading phase at month 3 and was maintained during the entire follow-up.

    Correlation between BCVA and central retinal thickness

    At baseline, there was a significant negative correlation between CRT and BCVA in the combination (p<0.001), but not in the monotherapy group (p=0.248). During follow-up, there was only a transient and modest correlation at month 9 (p<0.05) in the monotherapy group. Overall, retinal thickness was not correlated with function consistently, particularly not during the maintenance phase (figure 2, table 1).

    View this table:
    Table 1

    Partial correlation coefficients between δ BCVA (difference to baseline) and δ CRT in the two treatment arms corrected for the influence of morphologic changes (IRC, SRF, and PED)

    Figure 2
    Figure 2

    Scatter plots showing correlation of best-corrected visual acuity (BCVA) and CRT in the combination (A) and the monotherapy group (B) at baseline, months 3, 6, 9 and 12.

    Prognostic value of morphologic parameters for functional outcome

    Change and time course of BCVA in patients presenting with different morphological features in all combinations (+/−IRC, +/−SRF, +/−PED) at baseline were analysed in both groups (figure 3). Total and relative numbers of patients showing different combinations of morphological parameters at baseline are summarised in table 2.

    View this table:
    Table 2

    Total and relative numbers of patients showing different combinations of morphological parameters

    Figure 3
    Figure 3

    Time course of BCVA ((Early Treatment Diabetic Retinopathy Study (ETDRS) letters) after combination (A) and monotherapy (B) in patients with different morphological parameters and combinations at baseline. BCVA, best-corrected visual acuity; +/−C, intraretinal cysts present/absent; +/−S, subretinal fluid present/absent; +/−P, pigment epithelial detachment present/absent. Blue lines: Patients without intraretinal cysts at baseline. Red lines: Patients with intraretinal cysts at baseline.

    Any combination of morphological parameters which included IRC at baseline (curves indicated in red) showed a significantly lower mean BCVA, when compared with features without IRC (curves indicated in blue). During treatment, BCVA improved significantly in both groups, however, mean BCVA of patients showing baseline IRC remained significantly lower than mean BCVA of patients without baseline IRC during the entire follow-up. PED and SRF at baseline demonstrated a negative effect on BCVA levels at baseline and during follow-up only in combination with IRC. This pattern was noted consistently in both groups. Numbers per group in this trial were too small for statistical group comparison (table 2), but were statistically assessed by including baseline status into the general estimation equation model. IRC (p=0.006) at baseline significantly reduced BCVA gain, while SRF (p=0.704) and PED (p=0.626) at baseline had no significant effect.

    Relevance of morphological parameters for ranibizumab retreatment frequency

    The overall number of ranibizumab injections at month 12 was comparable between the treatment goups as reported earlier, with 4.9 ranibizumab injections in the combination group versus 5.2 injections in the monotherapy group.6

    The cumulative dose of ranibizumab in patients showing different morphological parameters (+/−IRC, +/−SRF, +/−PED) at baseline was analysed in both groups (figure 4). At month 12, patients with IRC at baseline showed a similar cumulative dose of ranibizumab when compared with patients without IRC at baseline in both arms (combination group: 5.0±2.3 injections vs 4.9±2.2 injections; monotherapy group: 5.2±2.0 injections vs 5.3±2.4 injections). There was no significant difference between the combination and the monotherapy group (p=0.31).

    Figure 4
    Figure 4

    Comparison of the mean cumulative dose of administered ranibizumab (500 µg/injection) in patients with and without intraretinal cysts (IRC) (A), with and without subretinal fluid (SRF) (B) and with and without pigment epithelial detachment (PED) (C) at baseline in the combination and the monotherapy group. Comparison of the mean cumulative dose of administered verteporfin (30 mL/infusion) in patients with and without IRC (D), with and without SRF (E) and with and without PED (F) at baseline in the combination group.

    Patients with SRF at baseline showed a significantly higher cumulative dose of ranibizumab at month 12 when compared with patients without SRF at baseline (p<0.01 combination group: 5.3±2.2 injections vs 4.4±2.3 injections; difference: 0.9 injections; monotherapy group: 5.6±2.4 injections vs 4.8±1.8 injections; difference: 0.8 injections).

    PED at baseline was associated with a significantly higher cumulative dose of ranibizumab in the monotherapy arm (p<0.01) (5.7±2.4 injections vs 4.5±1.5 injections; difference: 1.2 injections), but not in the combination group (5.0±1.9 injections vs 4.9±2.7 injections; difference: 0.1 injections).

    Relevance of morphological parameters for verteporfin PDT retreatment frequency

    A mean number of 1.7 verteporfin PDT treatments in the combination group until month 12 was performed.6

    Analysis of the cumulative dose of verteporfin PDT in patients showing different morphological parameters (+/−IRC, +/−SRF, +/−PED) at baseline showed no significant difference between patients presenting with or without IRC at baseline (2.0±1.1 treatments vs 1.8±1.0 treatments; difference: 0.2 treatments) (p=0.51) and no significant difference between patients with or without PED at baseline (1.8±0.9 treatments vs 2.0±1.2 treatments) (p=0.78).

    Only patients with SRF at baseline showed a tendency (p=0.09) for a higher verteporfin PDT treatment rate than patients without SRF at baseline (2.0±1.0 treatments vs 1.7±1.0 treatments; difference: 0.3 treatments) (figure 4).

    Discussion

    In the present study, OCT-derived biomarkers, such as CRT and defined morphologic parameters (IRC, SRF, PED) were documented over a 12-month period in ranibizumab monotherapy and combination treatment with verteporfin PDT plus ranibizumab in a prospective randomised trial. Reliable and solid OCT data were generated by certified graders in a standardised reading centre setting and correlated with BCVA.

    During the loading phase, the reduction of SRF and IRC was significantly more intensive with combination treatment than with monotherapy. This difference might be explained by the previously described choroidal hypoperfusion visible on indocyanine green angiography induced by verteporfin PDT.21 Transient vascular occlusion may diminish the ability of the CNV to leak fluid, while the retinal pigment epithelium (RPE) is pumping out accumulated intraretinal and SRF. Ranibizumab should have a synergistic effect in further diminishing the leakage activity of the neovascular net at 4 weeks after combination treatment.

    The more intensive reduction of PED with combination therapy might be explained by conversion of fibrovascular PED into a dry fibrotic lesion by verteporfin PDT. Induction of retinal fibrosis after verteporfin PDT in nAMD was previously described by OCT imaging, however, findings were not correlated with the presence of PED at baseline.15

    Partial correlation coefficients between δ BCVA (difference to baseline) and δ CRT were calculated at baseline, months 3, 6, 9 and 12 for both treatment groups. While an initial correlation of increased CRT and decreased BCVA could be demonstrated at least in the combination group, this association was absent in the monotherapy group already at baseline, missing consistently throughout the entire follow-up in both groups, and only occurred weakly and transiently at a single interval. Given the considerable large number of patients included and the stringent inclusion criteria ensuring comparable patient populations in both treatment groups, these findings provide further evidence that even accurate measurements of CRT fail to predict VA. This conclusion also applies to different therapeutic mechanisms used. CRT has been the most prominent per protocol criterion guiding PRN treatment in clinical studies, which may explain failure of PRN regimen to achieve optimal visual gains.

    A recent study analysed baseline predictors for 1-year visual outcomes with ranibizumab or bevacizumab for nAMD in the Comparison of Age-related Macular Degeneration Treatments Trials study. Older age, better baseline BCVA, larger CNV area, predominantly or minimally classic lesion, absence of retinal angiomatous proliferation lesion, presence of geographic atrophy, greater total fovea thickness, and RPE elevation on OCT were independently associated with less improvement in BCVA at 1 year.22 The substantial impact of IRC on retinal function during anti-VEGF monotherapy has been elucidated in other studies.14 ,23 The present study provides a detailed analysis of the impact of all combinations of morphological parameters at baseline on the course of BCVA during mono and combined therapy. In both treatment arms, patients with IRC at baseline showed the lowest initial level of VA and IRC also had the strongest negative predictive value for functional improvement over the entire study period. PED and SRF showed a negative predictive value for visual outcome only in combination with IRC. These findings suggest that cystic changes of the retina at baseline may indicate pre-existing retinal damage or a more aggressive form of CNV, decreasing the potential for visual gain which, furthermore, is independent of the therapeutic strategy and occurs similarly during antiangiogenic therapy and PDT.

    Another possible explanation for the finding that mean BCVA of patients showing IRC at baseline remained significantly lower than mean BCVA of patients without IRC at baseline during the entire follow-up may be that IRC was not considered as a retreatment criterion in the study protocol resulting in a possible undertreatment of this group of patients. Analysis of the relevance of morphological parameters for retreatment frequency showed that IRC at baseline have no predictive value for retreatment frequency, whereas SRF showed a significant predictive value for a higher number of ranibizumab injections in both treatment groups and a higher number of verteporfin PDT in the combination group. This finding results from the fact that SRF was an independent retreatment indicator.

    The finding that PED at baseline was associated with a higher number of ranibizumab injections only in the monotherapy group is unexpected. Additional verteporfin PDT, however, led to enhanced resolution of PED, thereby reducing the number of ranibizumab reinjections by occluding PED-harbouring CNV and associated serous exudation. In this respect, patients showing PED at baseline might benefit more from combination than from monotherapy, even though combination therapy did not result in higher levels of BCVA at the end of the study, neither in the subgroup with SRF nor PED.

    Overall, and this is probably the most important finding of this study, IRC was the over-ruling prognostic factor for both therapeutic strategies. Combination of antiangiogenic therapy with vaso-occlusive PDT achieved improved resolution of IRC, SRF and PED, nevertheless, in terms of functional benefit, antiangiogenic monotherapy was equal (MONT BLANC) or superior (DENALI) to combination therapy.6 ,7

    Limitations of the study include the use of time-domain OCT and the lack of quantitative data of IRC, SRF and PED, which could lead to a more accurate correlation of OCT morphology to visual function and retreatment frequency. In addition, the integrity of photoreceptor layers, presence of geographic atrophy and the integrity of the retinal pigment epithelium was not assessed, parameters which have been shown to be of importance for visual outcomes after anti-VEGF treatments.22 ,24

    In conclusion, this study shows that a precise understanding of the impact of alterations in retinal morphology on visual function is essential to understand the efficacy of any therapeutic strategy. Our findings further elucidate a reasonable path for an optimal PRN design, largely independent of the selected type of therapeutic intervention and the importance of identification of relevant qualitative OCT-based parameters.

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    Footnotes

    • Contributors Design and conduct of the study (MR, CS, MB, GGD, UMS, RS and UMS-E), collection and management of the data (CS, MB, GGD, UMS, RS and MK), analysis and interpretation of the data (MR, CS, MK and UMS-E), preparation of the manuscript (MR), and review of the manuscript (CS, MK and UMS-E).

    • Competing interests The data presented in this paper are the result of independent subanalysis of the MONT BLANC study conducted by the Vienna Reading Center (VRC) without any financial support. The Department of Ophthalmology at the Medical Universitiy of Vienna served as a clinical site in the MONT BLANC study and received regular recompensation for contract research. The sponsor or funding organisation had no role in the design or conduct of this research. UMS-E was a principal investigator in the MONT BLANC trial, Christian Simader is the director of the Vienna Reading Center (VRC) that performed OCT data analysis during the MONT BLANC study.

    • Patient consent Obtained.

    • Ethics approval Ethics Committee of the Medical University of Vienna.

    • Provenance and peer review Not commissioned; externally peer reviewed.