4 Australian Orthoptic Journal

Real-World Visual Outcomes of Treatment-

Naive Patients with Diabetic Macular Oedema
Meri Vukicevic BOrth PhD1
Czarina Obtinalla BAppSc MOrth2
Nandor Jaross MD FRANZCO PhD2

1
Discipline of Orthoptics, School of Allied Health Human Services and Sport, La Trobe University, Melbourne, Australia
2
Australian Eye Specialists, Werribee, Australia

ABSTRACT Keywords: diabetic macular oedema, anti-VEGF, real-world

outcomes, treatment naive eyes
Aim: The aim of this audit was to determine whether patients
with diabetic macular oedema attending a routine clinical INTRODUCTION
practice were able to achieve and maintain the visual outcomes
reported by clinical trials. It is estimated that 1.7 million Australians have diabetes and
associated eye disease, namely diabetic retinopathy (DR) which
Methods: A retrospective observational study of 131 treatment- is the most commonly reported complication. All individuals
naive eyes of patients attending one suburban and one semi- with type 1 and type 2 diabetes are at risk of developing DR with
rural ophthalmology clinic, in or close to Melbourne, Australia. the duration of diabetes being the most significant factor. Sight-
Data were extracted from the Diabetic Macular Oedema module threatening complications of retinopathy occur due to diabetic
of the Fight Retinal Blindness! Registry1 from 2014 to 2020. Main macular oedema (DMO) which causes swelling of the retina and
outcome measures included diabetic retinopathy characteristics accumulation of extracellular fluid in the macula.2-6
at baseline, pre-existing ocular conditions, previous treatments,
current treatment given, visual acuity, and central subfield Both intravitreal injections of corticosteroids and/or vascular
thickness. endothelial growth factor (VEGF) inhibitors are the current
treatment options for DMO. Triamcinolone acetonide and
Results: The average number of treatment injections was 5.58 intravitreal dexamethasone implant (Ozurdex) corticosteroids
in the first 12 months, compared with 5.51 beyond 36 months have been reported to reduce DMO and improve visual
(p>0.05). Eighty percent of patients had a baseline visual acuity outcomes. Whilst corticosteroids require reduced injection
of better than 6/12 and there was a statistically significant frequency compared with VEGF inhibitors, they are associated
improvement in acuity from baseline to Year 1, Year 2 and Year 3 with side effects such as cataract development and increased
(p<0.05). Baseline central serous thickness was 340.58µm and intraocular pressure.7-10 VEGF inhibitors include ranibizumab,
improved significantly at each time point (p<0.05). aflibercept and bevacizumab. Phase 3 randomised control
trials for DMO indicate that patients demonstrate significant
Conclusion:  Patients attending this routine clinical practice in improvement in visual acuity (VA). Better visual gains are
the real world were not able to achieve and maintain the visual reported in patients whose starting VA is poor, that is 6/24 or
outcomes reported by the phase 3 clinical trials. This is most less.7,9,11-14
likely due to under-treatment and suggests that the dosing
schedule for patients with diabetic macular oedema should be Despite the improvements in visual gains reported in clinical
re-evaluated. trials, real-world data from patients in the clinical setting,
evaluating the use of VEGF inhibitors indicates that patients
with DMO receive significantly fewer injections and smaller
visual gains, suggesting that these patients may not be
receiving optimum care.15,16 Diabetic patients are more likely to
Corresponding author: Meri Vukicevic
Discipline of Orthoptics miss an appointment compared to patients with neovascular
School of Allied Health Human Services and Sport age-related macular degeneration (nAMD) who undertake a
La Trobe University VIC 3086 Australia similar treatment regime.17-19 The risk of sub-optimal treatment
Email: [email protected]
Accepted for publication: 17th March 2021
is progressive retinal damage, reduced vision and ultimately
blindness.20,21 The difference in reported visual gains may be

Vukicevic et al: Real-world treatment outcomes with diabetic macular oedema: Aust Orthopt J 2021 Vol 53 © Orthoptics Australia
 Australian Orthoptic Journal 5

due to the strict treatment schedule of clinical trials, exclusion of parametric equivalent in the event that data assumptions were
patients with comorbidities and VA cut-offs at 6/9 to 6/12.16,22 A violated and not normally distributed. The level of significance
recently published guideline for the treatment of DMO suggests was set at α=0.05.
the necessity of a significantly increased number of treatment
injections compared to an initial loading dose followed by The procedures used for this audit adhered to the ethical
injections every 4-8 weeks until the oedema is resolved.22 responsibility requirements of the FRB! Project and followed the
Cheung et al22 indicate that further clarification of the treatment tenets of the Declaration of Helsinki. Patients provide consent at
regime is needed, particularly given the ‘common perception their first visit to the practice that their de-identified data may be
is that, because anti-VEGF therapies have now been used used for the purposes of clinic audits. With respect to the FRB!
for nAMD, the principles of treatment applied to AMD may be database, the design of the FRB! Project ensures maximum
extrapolated to DME. However, nAMD and DME differ vastly data security and anonymity1 and has received ethical
in their pathophysiology, clinical presentation, natural history, approval from the Royal Australian and New Zealand College of
treatment goals and outcomes’. Ophthalmologists’ Human Research Ethics Committee.

The aim of this audit was to determine whether patients with RESULTS
DMO attending a routine clinical practice were able to achieve
and maintain the visual outcomes reported by the phase 3 Disease characteristics and treatments
clinical trials which compared the use of anti-VEGF therapies. Over half of the eyes in this study (53.8%) were classified
with mild (36.9%) or moderate DR (16.9%). 28.5% of eyes
METHODS had severe non-proliferative DR and 18% of eyes had either
low-risk proliferative DR (15.4%) or high-risk proliferative DR
This was a retrospective observational study of patients (2.3%). Overall, 3,165 visits were recorded for this audit and
attending one suburban and one semi-rural ophthalmology treatment was administered on 1,457 occasions (46%) with
clinic, in or close to Melbourne, Australia. Patients were monitoring occurring on 1,708 occasions (54%). Aflibercept
undertaking treatment for DMO with one ophthalmology was administered more frequently compared with any other
consultant. The treatment protocol for DMO generally used at treatment option (Table 1). Referral to the patient support
this clinic involved three loading doses of anti-VEGF and if DMO program associated with aflibercept is actively encouraged as
persists after the third injection, monthly injections are given part of normal clinic protocol and patient uptake of this support
until the retina is free of fluid. Patients are then monitored at program appeared to be high. An internal clinical audit of
regular intervals; initially monthly for the first three months and referrals to the aflibercept ‘Smart Sight’ program indicated that
then, based on fluid dynamics and VA, the interval is extended 88% of patients accepted the referral.
on an individual-needs basis. Other necessary treatment, such
as peripheral retinal laser or corticosteroids, is given as required. Table 1. Treatment visits by type
Treatment administered Number of occasions %
Single-user non-identifiable data pertaining to these patients Aflibercept 1,019 69.9
were extracted from the DMO module of the Fight Retinal Ranibizumab 95 6.5
Blindness! (FRB!) Registry.1 Extracted data used for this analysis Bevacizumab 67 4.6
included DR characteristics at baseline, pre-existing ocular Ozurdex 46 3.2
conditions, previous treatments, current treatment given,
Triamcinolone 3 0.2
number of letters read on a logarithm of the minimum angle of
Peripheral retinal laser 227 15.6
resolution (logMAR) vision chart, and central subfield thickness
Total 1,457 100
(CST) using spectral-domain optical coherence tomography
(SD-OCT) (Zeiss, Germany). Data from 284 eyes treated for Thirty-nine eyes received treatment for up to 52 weeks before
DMO was extracted from the FRB! database from 11 June 2014 discontinuing and the number of treatment occasions was
to 3 July 2020. A total of 131 treatment-naive eyes (RE = 66; LE = 797, with a mean of 20.4 treatments per eye. The number of
65) of 131 patients were included for data analysis. One hundred eyes receiving treatment for 104, 156 and 208 weeks was 24,
and fifty-three eyes were excluded on the basis of previous 37 and 19 respectively and only 10 eyes received treatment for
treatment for DMO. 260 weeks. When corrected for loss to follow-up, the average
number of treatments per eye was stable, 5.58 in the first 12
All patient outcomes were included in the analysis, irrespective months, compared with 5.51 beyond 36 months (Wilcoxon
of whether they had been lost to follow-up. Statistical analyses Signed Rank Test: p>0.05). The reason for discontinuation of
were performed using IBM SPSS Statistics for Windows, treatment was related to a variety of factors including that they
Version 25.0. Armonk, NY. Comparison of means testing was were deceased, relocated a significant distance from the clinic
performed using dependent and independent t-tests or a non- or were unable to be contacted after missing an appointment.

Vukicevic et al: Real-world treatment outcomes with diabetic macular oedema: Aust Orthopt J 2021 Vol 53 © Orthoptics Australia
 6 Australian Orthoptic Journal

Visual acuity and central subfield thickness Table 3. Proportion of eyes with gain or loss of ≥10 letters
The time range used to analyse time periods for both VA and CST or ≥15 letters
were baseline (0-30 days), 1 year (10-14 months), 2 years (22-26 52 weeks 104 weeks 156 weeks
months), 3 years (34-38 months), 4 years (56-50 months), and 5 Vision gain, n (%)
years (58-60 months). VA and CST over time is shown in Table ≥15 letters 13 (10.3) 11 (13.1) 5 (11.1)
2. Mean baseline VA was 69.94 letters (6/12). Eighty percent
≥10 letters 22 (17.4) 19 (22.6) 11 (24.4)
of patients had a baseline VA of better than 70 letters (6/12);
Vision loss, n (%)
11.2% had baseline VA of 56 to 69 letters (6/12-6/19) and 5.6%
and 3.2% had baseline VA of 25 to 55 letters (6/24-6/60) and ≥10 letters 11 (8.7) 9 (10.7) 2 (4.41)
0 to 35 letters (<6/60), respectively. A means comparison was ≥15 letters 5 (3.9) 4 (4.7) 4 (8.8)
conducted to determine whether there was a significant change
in VA and the change in letters is shown in Figure 1. There was
a statistically significant improvement in VA score from baseline 0
to Year 1 (p=0.000), baseline to Year 2 (p=0.000) and baseline
-10
to Year 3 (p=0.009). At Year 4, VA improved by 5.34 letters and
the improvement from baseline to Year 5 was almost 10 letters, -20

Change in CST (microns)

however despite this apparent improvement, it did not reach -30
statistical significance, likely due to the very small proportion of -41.99
-40 -44.73
treatment-naive eyes that were still continuing treatment at this -45.86 -47.39
time, thereby affecting analysis. -50

-60
The proportion of eyes that gained or lost either ≥10 letters or -69.58
≥15 letters by 52 weeks, 104 weeks and 156 weeks is shown in -70
Table 3.
-80
Year 1 Year 2 Year 3 Year 4 Year 5
Baseline CST was 340.58µm and improved significantly Figure 2: Change in CST over time.
to 295.72µm at Year 1 (p=0.003) and eyes demonstrated
statistically significant improvement of -41.99µm from baseline
to Year 2 (p=0.001). Significant change in CST was also found
from baseline to Year 3 (p=0.000), Year 4 (p=0.009) and Year 5
12 (p=0.037). The change in CST from baseline to all time points
9.73 for these treatment-naive eyes is shown in Figure 2.
10

DISCUSSION
Change in VA (letters)

5.83 5.34
6 5.31 The aim of this retrospective audit of 131 treatment-naive
4.43
eyes was to determine whether patients with DMO attending a
4 routine clinical practice were able to achieve and maintain the
visual outcomes reported by the phase 3 clinical trials.
2

0 Over half of the patients in this study had mild or moderate DR

Year 1 Year 2 Year 3 Year 4 Year 5 and their baseline VA was 69.94 letters (6/12), with the majority
of eyes having a baseline VA of 70 letters or better. Baseline VA
Figure 1. Change
Change in
in VA
VA letters
lettersover
overtime.
time.

Table 2. Visual acuity and central subfield thickness, over time

Baseline Year 1 Year 2 Year 3 Year 4 Year 5
VA Mean 69.94 74.37 75.25 75.77 75.28 79.67
(SD) (17.08) (14.06) (10.93) (10.65) (9.11) (5.17)
Change from baseline +4.43 +5.31 +5.83 +5.34 +9.73
CST Mean 340.58 294.72 298.59 295.85 293.19 271.0
(SD) (103.63) (79.98) (97.71) (60.98) (51.02) (30.53)
Change from baseline -45.86 -41.99 -44.73 -47.39 -69.58

Vukicevic et al: Real-world treatment outcomes with diabetic macular oedema: Aust Orthopt J 2021 Vol 53 © Orthoptics Australia
 Australian Orthoptic Journal 7

in this study was better than that reported by other studies.16,23,24 The average number of injections administered per year as
Visual gains achieved by patients in this study ranged from 4 to reported by the VIVID and VISTA trials was approximately ten,
almost 6 letters over time and was better than that reported in a similar to the DRCR.net Protocol T study. In comparison, the real-
similar real-world retrospective audit where vision improved by world audit study by Biechl16 reported a mean of 17 treatment
a mean of 2.9 letters.16 When comparing outcomes stratified by injections over the full five years (approximately 3.4 per year). In
baseline VA reported by Biechl,16 eyes with a starting VA of ≥70 our study the mean number of treatments administered per year
letters lost an average of 3.2 letters at 5 years. Despite better was five, which is significantly less compared to the clinical trials
visual gains in this study compared to the real-world audit, and may account for the inferior visual gains in this cohort of
when compared with the VIVID, VISTA and DRCR.net Protocol DMO patients. Table 5 shows a summary of these outcomes and
T studies,12,14,23,24 patients in our study were not able to approach also includes the number of eyes with ≥15 letters improvement,
the reported visual acuity gains which were double in these which is also significantly more in the clinical trials.
trials. It is possible that eyes with worse acuity yield better visual
gains22 although this was not the case in the DRCR.net Protocol The outcomes of this audit indicate that patients attending a
T study, which reported the visual gains were similar irrespective routine clinical practice in the real-world are not able to achieve
of baseline acuity.24 The reason for a lower improvement in and maintain the visual outcomes reported by the phase 3
vision in this study may be related to better baseline acuity, clinical trials. The difference may be related to the baseline
particularly as visual gains reported in the real-world audit by VA and CST, but we suggest it is more likely due to under-
Biechl16 were also not as great as the clinical trials. treatment. Cheung et al22 suggest that patients with DMO be
treated intensively and as early as possible, with at least five
The number of eyes achieving an increase or decrease of to six monthly loading doses of VEGF inhibitors, with a view
10 or 15 letters in this study (Table 3) is significantly less to administering eight to nine injections over a twelve-month
than that reported by the VIVID, VISTA or DRCR.net Protocol period before decreasing the injecting rate in subsequent years.
T studies.12,14,23,24 These authors report that 35 to 77% of Whilst the guidelines proposed by Cheung et al22 are for an Asian
participants in these clinical trials were able to achieve a gain population, it is worth considering that a significant number of
in vision of 15 letters or more and only a small proportion (up patients with DMO of varying race are being significantly under-
to 6.5%) lost 15 letters or more. Whilst the proportion of loss treated in the real-world setting.
of acuity was similar in this study, the visual gains of 15 letters
or more were significantly less. This may be due to the higher What are the reasons for under-treatment? Anecdotal clinical
proportion of patients (80%) with a good baseline acuity of 70 evidence suggests that the setting of treatment expectations
letters (6/12), although if baseline acuity is 6/12, a 15 letter to the patient at their initial presentation is not sufficiently
increase to 6/6 (85 letters) is achievable. When compared effective. An injecting schedule of at least five to six monthly
with real-world data, the proportion of eyes achieving an loading doses and up to nine injections per year is a ‘hard sell’
improvement of ≥15 letters (10-11%) in this study is still lower to a patient cohort that has issues with non-adherence due to
than the 17% who gained ≥15 letters, as reported by Biechl.16 costs, needing to take time off work, or burden on family.17-19 In
addition, some patients choose to live with slightly sub-optimal
Baseline CST in this study was 340µm and the improvement vision in exchange for a lower number of injections as a trade-
at each time-point ranged from 42 to 69µm. Like the study off, and therefore do not return for continuing management of
by Biechl,16 the improvement in CST was significant, despite their disease.
the modest improvements in VA. The change in thickness
however, was lower when compared with the real-world audit The limitations of this study include that the number of patients
and the VIVID, VISTA or DRCR.net Protocol T studies and is is significantly lower than those in clinical trials12,14,23,24 and
likely due to the smaller thickness at baseline in this cohort of in another retrospective real-world audit.16 The analysis of
patients.12,14,16,23,24 only treatment-naive eyes may also have an influence on the

Table 4. Summary of outcomes between our study and others

Our study Real-world retrospective audit VIVID & VISTA clinical trials DCR.net Protocol T
(Biechl et al, 2020)16 (Heier et al, 2016)12 (Wells et al, 2016)14

Visual gains (letters, n) +4 - +6 +2.9 +10 +9.7 - +13.3

Mean number of injections 5 3.4 18 - 29 13.4 - 14.3

# eyes with ≥15 letters (%) 10 - 11 17 40 - 50 52 - 58

Vukicevic et al: Real-world treatment outcomes with diabetic macular oedema: Aust Orthopt J 2021 Vol 53 © Orthoptics Australia
8 Australian Orthoptic Journal

outcomes reported in this cohort as other studies have included 9. Michaelides M, Kaines A, Hamilton RD, et al. A prospective
eyes with previous treatment for DMO. This study has included randomized trial of intravitreal bevacizumab or laser therapy in the
management of diabetic macular edema (BOLT study) 12-month
patients that received other treatments, not just VEGF inhibitors
data: report 2. Ophthalmology 2010;117(6):1078-86.e2.
and whist the majority of treatments were VEGF inhibitors, this
10. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study:
may have affected the results. The outcomes may also have
phase 2 primary results of VEGF Trap-Eye in patients with diabetic
been affected by the treatment decisions made in the real-world macular edema. Ophthalmology 2011;118(9):1819-1826.
clinic that rely on a different set of patient outcomes compared
11. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating
to clinical trials that require scheduled dosing and rely on image ranibizumab plus prompt or deferred laser or triamcinolone
reading centres. plus prompt laser for diabetic macular edema. Ophthalmology
2010;117(6):1064-77.e35.
Future studies that explore real-world outcomes in patients 12. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept
with DMO are essential. Also, research to investigate the for diabetic macular edema: 148-week results from the VISTA and
VIVID studies. Ophthalmology 2016;123(11):2376-2385.
impact of easing the burden of repeated treatment and its cost,
combined with amending the treatment protocol for diabetic 13. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic
macular edema: results from 2 phase III randomized trials: RISE
patients will add to the understanding of real-world outcomes.
and RIDE. Ophthalmology 2012;119(4):789-801.
Further research will also show whether increasing injections
14. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab,
and amending the protocol will make a difference in terms of or ranibizumab for diabetic macular edema: two-year results
outcomes for these patients. from a comparative effectiveness randomized clinical trial.
Ophthalmology 2016;123(6):1351-1359.
ACKNOWLEDGEMENTS 15. Sivaprasad S, Oyetunde S. Impact of injection therapy on retinal
patients with diabetic macular edema or retinal vein occlusion. Clin
This research project was supported by a grant from Bayer Ophthalmol 2016;10:939-46.
Australia Ltd. The authors would like to acknowledge Shannon 16. Biechl A, Bhandari S, Nguyen V, et al. Changes in real‐world
treatment patterns for diabetic macular oedema from 2009 to
Brown, Lauren Moussalem and Dhanushka Galister for their
2019 and 5‐year outcomes: data from the Fight Retinal Blindness!
assistance on this project.
Registry. Clin Exp Ophthlamol 2020;48(6):802-12.
17. Best AL, Fajnkuchen F, Nghiem-Buffet S, et al. Treatment
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Vukicevic et al: Real-world treatment outcomes with diabetic macular oedema: Aust Orthopt J 2021 Vol 53 © Orthoptics Australia