Rod McNeil

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Reviewed by Dr Marko Lukic and Dr Thomas A Ciulla

One-year results from a retrospective cohort study that assessed the effectiveness of aflibercept (Eylea, Regeneron Pharmaceuticals) in treatment-naïve patients with diabetic macular oedema (DMO), conducted at Moorfields Eye Hospital, London, compare favourably to outcomes seen in randomised clinical trials (Figures 1 and 2).

 Follow-up over 36 months further confirmed maintenance of vision long term with continued retreatment if needed.

At 3 years, eyes with worse visual acuity (VA) at baseline (<69 early treatment diabetic retinopathy study [ETDRS] letters), accounting for 58% of the study cohort, achieved greater than a two-line vision gain (+11.27 letters) from baseline, while stable vision was maintained in eyes having initially better VA (69–80 letters). Some 89% of patients overall received the recommended treatment initiation protocol of five consecutive monthly injections.

Lead author of both studies, Dr Marko Lukic, explained: “Clinical trials provide what I term the ideal results with respect to treatment efficacy and safety. Real-world studies provide us with more realistic results of treatment effectiveness in everyday practice using practical protocols.”

He added: “At month 36, one quarter of eyes gained at least three lines of vision from baseline and the final mean VA was around 69 ETDRS letters, meeting driving criteria.”

Overall, the mean VA gain was 9.9 letters with a mean of 6.9 injections over 12 months. The independent DRCR.net Protocol T study showed better improvements in VA with an average of nine injections in the first year.

 However, following strict protocols suggested by clinical trials is difficult to maintain in real-life settings, remarked Dr Lukic.

We mostly commence treatment of new patients with DMO using intravitreal aflibercept injections and always aim to provide five initial monthly injections and then treatment as needed, which for most patients means three bimonthly injections and an average of seven to eight injections in year one. It is important to secure the maximum vision improvement in the first year and, after that, to maintain stable vision with retreatment as needed.”

“We divided our study cohort into two subgroups according to baseline VA and showed that those with worse baseline VA (<69 letters, 20/50 or worse) had greater vision gains than those with better presenting vision. However, those with baseline VA ≥69 letters still achieved good maintained vision. And overall, when you compare these two subgroups, those who commenced treatment earlier (i.e., with better VA at baseline) had better results in terms of final VA letter score (approximately 75 vs. 63 letters, respectively, at month 36).”

If continuity of anti-vascular endothelial growth factor (VEGF) treatment for DMO is maintained and if there is no presence of significant macular ischaemia, then Dr Lukic believes good vision outcomes can be routinely achieved in everyday practice. Adherence to the initiation protocol of monthly loading followed by bimonthly injections in year one is extremely important, he said.

Dr Lukic added: “Diabetic macular oedema is a chronic condition and regular retreatment is needed for most patients. Retreatment beyond year one is led largely by optical coherence tomography appearance, i.e., those with persistent fluid or who develop new fluid continue to receive retreatment.”

“Some patients received more than three injections over both year two and year three. On the other hand, 13% of aflibercept-treated eyes received no further injections beyond the loading phase by the end of 3 years since initiation of treatment.”

There is always a small subgroup of patients who do not respond as expected and who may need to be switched to another treatment (e.g., 3/102 aflibercept-treated eyes in the cited 12-month study), Dr Lukic said. “Steroids may have a role in selected cases, for example, pseudophakic eyes with refractory or persistent DMO despite continued anti-VEGF therapy.” 

In a large real-word study in the United States, it was found that patients with DMO consistently achieved poorer vision outcomes and received fewer anti-VEGF injections than those in randomised clinical trials. A retrospective electronic medical record (EMR) database analysis of 28,658 treatment-naïve eyes treated with anti-VEGF for DMO from 2013 to 2018 found a mean VA gain of 4.2 letters with a mean of 6.4 injections over 1 year.

 This large sample of DMO patient eyes included all-comers who received at least one anti-VEGF injection and had 12-month follow-up data.

Half of all patient eyes received six or fewer injections over the year. Vision outcomes correlated with treatment intensity and, as expected, mean letter gains were higher in those with poorer starting vision. Outcomes similar to clinical trials were achieved in a subgroup of patients with moderately severe baseline visual impairment (20/70 to 20/200), showing a 1-year gain of 10.3 letters with ≥10 injections (from a mean baseline VA of 47.2 letters).

Commenting on the persistent reported gap between clinical trials and real-world outcomes, lead study investigator Dr Thomas A, Ciulla explained: “Our findings showing only limited vision improvement are attributed largely to two key factors: first, real-world patients differ from those in clinical trials and second, they are undertreated with a lower frequency of anti-VEGF injections.”

Patients with DMO can have chronic advanced oedema with ischaemia and atrophy, while some present with very good VA, Dr Ciulla said. “But even if real-world DMO patients differ from clinical trial participants, we should do everything we can for them: encourage them to comply with recommended treatment regimens and make sure they receive an appropriate level of treatment intensity.”

“Our data suggest that, to maximise real-world outcomes, the average DMO patient requires intense anti-VEGF therapy during the first year of treatment,” added Dr Ciulla. “Moreover, vision gains generally approach a plateau at a treatment frequency of nine or more injections in year one.” Slightly better overall outcomes were previously reported in another US EMR database study of DMO eyes that underwent ≥3 monthly anti-VEGF injections within 4 months of the first injection, where the mean 12-month visual improvement was 5.5 letters.

Importance of complete treatment initiation schedules

In France, a prospective cohort study (APOLLON) of aflibercept in private and public clinical practice showed improvements in functional and anatomical outcomes over 12 months in both treatment-naïve and previously treated patients with DMO (Figure 3).

The mean (SD) change in best-corrected visual acuity was +7.8 (12.3) letters in treatment-naïve patients and +5.0 (11.3) letters in previously treated patients at month 12, with patients receiving a mean of 7.6 injections, slightly lower than that in the aflibercept DMO registration trials. The proportions gaining 15 letters or more from baseline were 29.9% and 18.6%, respectively.

Of note, only 42.2% (n=62) of the study cohort received the complete five initial monthly doses as indicated in the label regimen. Table 1 shows visual outcomes stratified by initial treatment exposure in the treatment-naïve cohort, with better visual outcomes achieved in patients receiving the recommended treatment initiation schedule.

“Great steps forward have been made in the management of retinal disease in the past decade,” observed Dr Ciulla. “However, many of our current modalities require fixed, frequent treatments and what we ultimately need is better treatments that last longer.”


Dr Lukic is a locum consultant ophthalmologist, National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. The research reported in this article was supported by the NIHR Biomedical Research Centre. He has no financial interests in the subject of this article.


Dr Ciulla is volunteer clinical professor of Ophthalmology at Indiana University School of Medicine, United States, a board member of Midwest Eye Institute, Indianapolis, and chief medical officer/chief development officer at Clearside Biomedical. Dr Ciulla has no financial interests in the subject of this article.

Lukic M, Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema: Moorfields' real-world 12-month visual acuity and anatomical outcomes. 

Lukic M, Gwyn Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema in real-world: 36-month visual acuity and anatomical outcomes. 

 19 May 2020. DOI:10.1177/1120672120925034.

The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. 

Ciulla TA, Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular edema: a real-world analysis of 28 658 patient eyes. 

. 7 Apr 2020. DOI: 10.1136/bjophthalmol-2020-315933.

Ciulla TA, Bracha P, Pollack J, Williams DF. Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States. 

Korobelnik JF, Daien V, Faure C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. 

Articles

Good early adherence to label regimens can make a difference, yielding vision outcomes approaching those in clinical trials, emerging real-world studies of anti-VEGF for DMO suggest. 

Emerging real-world evidence of anti-VEGF for diabetic macular oedema

This article was reviewed by Prof. Martin S. Zinkernagel

Anti-vascular endothelial growth factor (VEGF) treatment regimens for neovascular age-related macular degeneration (nAMD) generally aim to dry the neovascular lesion, but evidence suggests that not all retinal fluid is the same. When fluid is present, intraretinal fluid (IRF) is associated with poorer vision.

However, some fluid, particularly subretinal fluid (SRF), may be tolerated.

Admittedly, questions about the impact of refractory SRF on visual outcomes, such as threshold values and duration, continue to be raised. Practitioners nonetheless agree that persistent (i.e., residual) IRF is bad for vision and requires aggressive treatment to maintain sight. At multiple international congress debates in recent months, advocates for and against the need for complete fluid resolution when treating nAMD have presented cogent arguments, shared below.

Based on current clinical data and clinical practicability, outcomes are best if all fluid is treated rigorously when using protocols other than a fixed dosing regimen, argued Prof. Martin Zinkernagel of the University of Bern, Switzerland, at the 19th European Society of Retina Specialists (EURETINA) Congress in 2019 in Paris, France. He pointed to multiple studies which show that improvement of vision correlates with a dry macula and that IRF correlates with poorer final vision.

A zero-tolerance approach to the presence of fluid in nAMD is encouraged, since patients who avoid fluctuations in fluid in the macula may have better visual outcomes. Higher central subfield thickness (CST) variability was associated with lower best-corrected visual acuity (BCVA) gains up until 96 weeks, according to pooled treatment and study data from an analysis of the Phase 3 HAWK and HARRIER nAMD registration studies.

 Although the amplitude of the BCVA gain is individual, more stable CST was associated with both better visual outcomes and a fluid-free retina.

Dr David Brown, Retina Consultants of Houston, United States, who spoke at the American Academy of Ophthalmology (AAO) 2019 Retina Subspecialty Day in October 2019 in San Francisco, US, also cautioned that visual outcomes in nAMD are poorer when fluid is tolerated. In the FLUID study of ranibizumab treat-and-extend for nAMD, up to 40% of patients had refractory IRF and the mean improvement in BCVA overall was no more than 3 letters at 24 months.

 Substantially better visual outcomes have been reported in other proactive anti-VEGF treat-and-extend studies.

Practitioner experience confirms that nAMD patients can tolerate a small amount of SRF with no detrimental effects on visual outcome and it may be helpful in some patients, observed Dr Ramin Tadayoni, Hopitaux de Paris, France, speaking at the 19th EURETINA Congress. Both baseline and persistent intraretinal cystoid fluid have a negative impact on visual acuity despite treatment, while SRF is associated with better outcomes and a lower rate of progression to geographic atrophy.

Eyes with SRF present at baseline had a higher visual acuity improvement than eyes without baseline SRF up to 96 weeks in the Phase 3 VIEW trials of aflibercept (Eylea, Bayer/Regeneron) for nAMD.

 Irrespective of treatment frequency, presence of SRF shows a stable association with better visual outcomes in nAMD.

Further supporting evidence comes from theComparison of Age-related Macular Degeneration Treatments Trials (CATT) study, which showed that foveal IRF is associated with worse visual acuity at year 5 and eyes with foveal SRF had better visual acuity at this time point than eyes that did not.

In the FLUID study, vision outcomes with ‘intensive’ treatment aiming for complete fluid resolution were not significantly better than those seen with a ‘relaxed’ regimen that tolerated some SRF (≤200 µm only at the foveal centre).

Not all retinal fluid is the same, argued Dr Joan Miller, Harvard Medical School, United States, who spoke at the AAO 2019 Retina Subspecialty Day. While some SRF may be tolerated with ongoing treatment, IRF indicates CNV activity and needs to be treated more assertively, she said.

Anatomic improvements (in particular, resolution of IRF) are closely associated with better visual outcomes in nAMD. Clinical studies show that stable subfoveal SRF may be associated with better visual outcomes than persistent IRF.

Recent evaluations from the HARBOR study showed that those patients with residual SRF have the best vision outcomes, suggesting that a dry retina does not necessarily correlate with the best vision gains.17 In a post-hoc analysis of the VIEW trials, eyes with early, persistent IRF were shown to have significantly poorer visual acuity gains than those without residual IRF (Figure 1).

 Furthermore, IRF but not SRF was found to have a detrimental impact on visual acuity over 52 weeks.

In the HAWK and HARRIER studies, superior anatomic efficacy outcomes seen for brolucizumab (Beovu, Novartis) with respect to retinal thickness and fluid did not translate to superior vision gains over standard-of-care aflibercept.

Recommendations on the use of fluid status to guide treat-and-extend regimen decisions with anti-VEGF therapy for nAMD, from a global collaboration of expert ophthalmologists and retinal specialists who presented at the Europe Controversies in Ophthalmology 2020 Virtual Conference (COPHy) in March 2020, are summarised in Table 1. Whilst IRF can be considered a biomarker of disease activity, some persistent SRF may be tolerated. Moreover, improving IRF and/or stable SRF can be managed using maintained or extended treatment intervals.

Treat-and-extend retreatment/extension decisions should differentiate between IRF and SRF to improve patient outcomes, as a zero-tolerance approach to SRF may not be required for optimal outcomes, considered Dr Paolo Lanzetta, University of Udine, Italy, at the 2020 COPHy. Moreover, maintaining or extending injection intervals in the presence of residual SRF can decrease overall patient burden by minimising treatment exposure, he added.

Real-world data suggests that some fluid, particularly SRF, may be tolerated without compromising visual outcomes with maintained retreatment in patients with treatment-naïve nAMD (Figure 2).

  If SRF persists but is stable despite intensive therapy and follow-up, only an increase in SRF may be clinically relevant.

Prof. Zinkernagel is a retina specialist based at the Department of ophthalmology at Bern University Hospital, Bern, Switzerland. He has no financial interest in the subject matter.

Wickremasinghe SS, Janakan V, Sandhu SS, et al. Implication of recurrent or retained fluid on optical coherence tomography for visual acuity during active treatment of neovascular age-related macular degeneration with a treat and extend protocol. 

Lai TT, Hsieh YT, Yang CM, et al. Biomarkers of optical coherence tomography in evaluating the treatment outcomes of neovascular age-related macular degeneration: a real-world study. 

Ritter M, Simader C, Bolz M, et al. Intraretinal cysts are the most relevant prognostic biomarker in neovascular age-related macular degeneration independent of the therapeutic strategy. 

Gianniou C, Dirani A, Jang L, Mantel I. Refractory intraretinal or subretinal fluid in neovascular age-related macular degeneration treated with intravitreal ranibizumab: functional and structural outcome. 

Grunwald JE, Daniel E, Huang J, et al. CATT Research Group. Risk of geographic atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials. 

Guymer RH, Markey CM, McAllister IL, et al. FLUID Investigators. Tolerating subretinal fluid in neovascular age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen: FLUID study 24-month results. 

Dugel PU. Pooled treatment study data for brolucizumab and aflibercept from HAWK and HARRIER. Presentation at the 19th EURETINA Congress, September 5-8, 2019, Paris, France.

Ohji M, Takahashi K, Okada AA, et al. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR. 

Kertes PJ, Galic IJ, Greve M, et al. Efficacy of a treat-and-extend regimen with ranibizumab in patients with neovascular age-related macular disease: a randomized clinical trial

. 2020 Jan 9. doi: 10.1001/jamaophthalmol.2019.5540. [Epub ahead of print]

Schmidt-Erfurth U, Waldstein SM. A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration. 

Waldstein SM, Simader C, Staurenghi G, et al. Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials. 

Schmidt-Erfurth U, Klimscha S, Waldstein SM, Bogunović H. A view of the current and future role of optical coherence tomography in the management of age-related macular degeneration. 

Jaffe GJ, Martin DF, Toth CA, et al. Comparison of age-related macular degeneration treatments trials research group. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. 

Jaffe GJ, Ying GS, Toth CA, et al. Comparison of age-related macular degeneration treatments trials research group. Macular morphology and visual acuity in year five of the Comparison of Age-related Macular Degeneration Treatments Trials. 

Schmidt-Erfurth U, Eldem B, Guymer R, et al. EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. 

Sulzbacher F, Roberts P, Munk MR, et al. Vienna Eye Study Center. Relationship of retinal morphology and retinal sensitivity in the treatment of neovascular age-related macular degeneration using aflibercept. 

Sadda SR. Relationship between subretinal fluid (SRF) or intraretinal fluid (IRF) and vision outcomes in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab in the HARBOR trial. Presentation at The Retina Society 2019 Annual Meeting, September 11-15, 2019, London, UK.

Singh RP. Association between early visual function outcomes and anatomic dryness in neovascular age-related macular degeneration. Presentation at The Retina Society 2019 Annual Meeting, September 11-15, 2019, London, UK.

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Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. 

Gillies MC, Nguyen V, Pilar C, et al. Association between anatomical and clinical outcomes in patients treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Presentation accepted for the Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting, May 2020.

Recent international ophthalmic congresses have featured advocates for and against the need for complete fluid resolution when treating nAMD, with some ophthalmologists arguing for a zero-tolerance approach to the presence of fluid, and others claiming some residual fluid can be tolerated and may be helpful in some patients. 

Author | Rod McNeil

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Emerging real-world evidence of anti-VEGF for diabetic macular oedema

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