DME management

Structure and Function in clinical Practice - Relationships between VA
and OCT metric of retinal thickness
• Visual Acuity is an important measure of function
• Visual Acuity merely reflects function at the preferred retinal
locus which is usually the fovea
• DME affects the entire macula
• Visual Acuity by itself therefore shows only modest correlations with OCT foveal
centre point thickness
DME: Diabetic Macular Edema; OCT: Optical Coherence Tomography; VA: Visual Acuity.
1. Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–536.

Change in OCT Center Point Does Not Correlate Well with Change in
Visual Acuity
Absolute Change in OCT Center
Point thickening (Microns)
-300
-200
-100
0
100
200
300
Change
in
Visual
Acuity
(Letters)
-30
-20
-10
0
10
20
30
Spearman Correlation: r = 0.40
N = 190
Thinner / VA Worse
Thicker / VA Worse
Thinner / VA Better
Thicker / VA Better
OCT: Optical Coherence Tomography; VA: Visual Acuity.
1. Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–536

Diabetic Macular Edema
• Inflammation is a major factor in the development of ME
• It is important to acknowledge its role in fluid accumulation as inflammation occurs
early, and before ME
• Therefore, early treatment can control inflammation and prevent the development of
the edema
ME: Macular Edema.
2. Sun J K, Lin MM, Lammer J, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol . 2014;132(11):1309–16.
3. Owen LA and Hartnett ME. Soluble Mediators of Diabetic Macular Edema: The Diagnostic Role of Aqueous VEGF and Cytokine Levels in Diabetic Macular Edema. Curr Diab Rep. 2013;13:476–480.
4. Cho H and Madu A. Etiology and treatment of the inflammatory causes of cystoid macular edema. J Inflamm Res. 2009;2:37–43.
5. Trichonas G and Kaiser PK. Optical coherence tomography imaging of macular oedema. Br J Ophthalmol. 2014;98(Suppl II):ii24-ii29.

DME – management options
*Not licensed for ophthalmological use; $ Not approved and not available in India; # Not approved for use in DME
DME: Diabetic macular edema; VEGF: Vascular Endothelial Growth Factor.
6. Mathew C, Yunirakasiwi A and Sanjay S. Updates in the Management of Diabetic Macular Edema. J Diabetes Res. 2015;2015:794036.
Anti-VEGF agents
Ranibizumab
Aflibercept
Bevacizumab*
Steroids
Dex Implant
Fluocinolone$
Triamcinolone#
Laser photocoagulation
Surgery
Vitrectomy

Points to consider in patient management
• Baseline VA
• Duration of DME (chronicity alters treatment responsiveness)
• The ocular environment and local pathological changes eg. ERM
• Systemic factors
• Variable treatment responsiveness to anti VEGF, steroid and laser suggests presence
of multitude of pathogenetic pathways
DME: Diabetic Macular Edema; ERM: Epiretinal Membrane; VA: Visual Acuity; VEGF: Vascular Endothelial Growth Factor.
7. Proposed by authors.

Treating patients in clinical trials and real-world scenarios
Characteristics of clinical trials:
• Limited by eligibility criteria (population characteristics)
• Study design (mainly addresses metrics of efficacy and potential safety events that
occur at high frequency)
• Adherence to protocol is mandatory
Challenges faced at introduction into practice:
• Wider population excluded from clinical trials
• Treatment continuation in the longer term and quality of life issues – Compliance issues
• Understanding outcomes in the presence of lack of adherence to protocol
• Burden of treatment for patients, care-givers, and providers
8. Garrison LP, Neumann PJ, Erickson P, et al. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value in Health. 2007;10(5):326–335.

Visual Improvement
Also depends on chronicity of DME
• Destruction and disorganization of retinal tissue
• VEGF increase is no longer the sole pathogenic mechanism
DME: Diabetic Macular Edema; VEGF: Vascular Endothelial Growth Factor.
9. Mushtaq B, Crosby NJ, Dimopoulos At, et al. Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular edema. Clinical Ophthalmology. 2014;8:807–812.
3. Owen LA and Hartnett ME. Soluble Mediators of Diabetic Macular Edema: The Diagnostic Role of Aqueous VEGF and Cytokine Levels in Diabetic Macular Edema. Curr Diab Rep. 2013;13:476–480.
2. Sun JK, Lin MM, Lammer J, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol . 2014;132(11):1309–16.

The need for real-world evidence
• The outcomes from clinical trials are rarely matched by real-world outcomes for
reasons previously outlined8
• Questions usually arise on:7
– If anti-VEGF agent used, which one should be used?
– Do the differences in baseline characteristics that influenced outcomes
in clinical trials show similar effects in the real world?
– Dosing regimens
– How concerned should we be about potential systemic side effects?
VEGF: Vascular endothelial growth factor.
8. Garrison LP, Neumann PJ, Erickson P, et al. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value in Health. 2007;10(5):326–335.

Which anti VEGF drug:
Protocol T Change in Visual Acuity Over 2 Years Baseline Visual Acuity 20/32 to
20/40
0
2
4
6
8
10
12
14
16
18
20
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Mean
Change
in
Visual
Acuity
Letter
Score
Weeks
Aflibercept Bevacizumab Ranibizumab
+8.0
+8.3
+7.5
+6.8
+8.6
+7.8
~50% of Cohort
†
* P-values adjusted for baseline visual acuity and multiple comparisons; † Not licensed for ophthalmological use.
VEGF: Vascular Endothelial Growth Factor.
10. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351–1359.
104-Week Treatment Group Comparison*:
Aflibercept vs. Bevacizumab† P = 0.51
Aflibercept vs. Ranibizumab P = 0.51
Ranibizumab vs Bevacizumab† P = 0.31

Protocol T Change in Visual Acuity Over 2 Years Baseline Visual 20/50
or Worse
0
2
4
6
8
10
12
14
16
18
20
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Mean
Change
in
Visual
Acuity
Letter
Score
Weeks
Aflibercept Bevacizumab Ranibizumab
Aflibercept vs. Bevacizumab† P = 0.02
Aflibercept vs. Ranibizumab P = 0.18
Ranibizumab vs. Bevacizumab† P = 0.18
+18.9
+14.2
+11.8
+13.3
+16.1
+18.1
~50% of Cohort
†
* P-values adjusted for baseline visual acuity and multiple comparisons. † Not licensed for ophthalmological use.

Protocol I Mean Change in Visual Acuity*
at Follow-up Visits (year 5)
+9.8
+7.2
Bevacizumab† prompt laser vs.
Bevacizumab† deferred laser P = 0.09
* Truncated to ± 30 letters, based on longitudinal analyses adjusting for baseline VA. † Not licensed for ophthalmological use.
11. The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2010;117(6):1064–1077.

Protocol I – Ranibizumab groups, Change in VA
Over 5 Years Stratified by Baseline VA
• Test for interaction at 5 Year time point: P = 0.001
• Test for interaction from longitudinal model: P = 0.004
VA: Visual Acuity.
11. The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2010;117(6):1064–1077.

Assessing the Association between Persistence of ME & VA Outcomes
in DME – A Post Hoc Analysis of Protocol I
Objective
• To assess the relationship between anatomic response to ranibizumab, measured by
duration of edema, and long-term visual acuity outcomes in DME
DME: Diabetic Macular Edema; ME: Macular Edema; VA: Visual Acuity.
12. Sadda SR, Campbell J, Dugel PU, et al. Relationship between duration and extent of oedema and visual acuity outcome with ranibizumab in diabetic macular oedema: A post hoc analysis of Protocol I data. Eye (Lond). 2020;34(3):480–490.
Images provided courtesy of Anat Loewenstein, Tel Aviv University, Israel.

Methods
Study population was stratified into four cohorts:
• Defined by duration of edema measured by cumulative number of visits (sequential or
non-sequential) with CRT ≥250 µm in first year:
– Cohort 1: 0-3 visits
– Cohort 4: 12-14 visits → persistent edema!
Outcome: VA response assessed by:
• Mean VA change from baseline at:
– Week 52
– Week 104
– Week 156
• Source of the data is the DRCR.net but the post-hoc analyses, content and conclusions are
solely the responsibility of the authors and have not been reviewed or approved by
DRCR.net
* Protocol I re-treatment allowed persistent edema to be observed if no further anatomic/functional response was seen with ranibizumab and laser (prompt or deferred).
CRT: Central Retinal Thickness; VA: Visual Acuity.

Duration of Edema in the First Year Post-Treatment Initiation: One-
third of study eyes showed persistent edema over the first year
23.2%
24.5%
19.1%
33.2%
0%
5%
10%
15%
20%
25%
30%
35%
Proportion
of
Patients
N=367
C1: 0-3 visits C2: 4-7 visits C3: 8-11 visits C4: 12-14 visits
C: Cohort.

Among eyes with the most persistent edema at week 52, edema
tended to persist over the second year
23.2%
24.5%
19.1%
33.2%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Cohort at Week 52:
Visits with CRT≥250µm
C1 C2 C3 C4
10.7%
9.8%
12.3%
67.2%
Cohort over Year 2:
Patients in C4 at
Week 52
89.4%
9.4%
Cohort over Year 2:
Patients in C1 at
Week 52
0-3 visits
4-7 visits
8-10 visits
11-13 visits
Correlation coefficient* = 0.742; P<0.001
*Correlation coefficient measuring correlation between percentage of visits in Year 1 versus percentage of visits in Year 2 with CRT ≥ 250 µm
C: Cohort; CRT: Central Retinal Thickness.

Eyes with the most persistent edema gained significantly fewer letters
at week 52
11.5
9.7 10.2
6.3
0
2
4
6
8
10
12
14
16
VA
Mean
Change
from
Baseline
at
Week
52
Cohort by Cumulative Visits with Edema (CRT≥250µm) at Week 52
Cohort 1 vs Cohort 4: P=0.001
C: Cohort; CRT: Central Retinal Thickness; VA: Visual Acuity.

Among eyes with the most persistent edema at week 52, poorer
visual acuity gains persisted at Week 104
10.5 10
10.6
5.9
0
2
4
6
8
10
12
14
Mean
VA
Change
from
Baseline
at
Week
104
Cohort by Cumulative Visits with Edema (CRT≥250µm) at Week
52
Week 104
9.5
8.6
9.3
6.9
0
2
4
6
8
10
12
14
C1: 0-3 visits C2: 4-7 visits C3: 8-11 visits C4:12-14 visits
Mean
VA
Change
from
Baseline
at
Week
156
Cohort by Cumulative Visits with Edema (CRT≥250µm) at
Week 52
Week 156
Cohort 1 vs Cohort 4: P=0.013 Cohort 1 vs Cohort 4: P=0.186

Vision improvement at both week 52 and 104 is lower in patients
with persistent edema
9.5
6.9
9.9
5.1
0
2
4
6
8
10
12
14
C1 at week 52
(N=85)
C4 at week 52
(N=122)
C1 at week 104
(N=111)
C4 at week 104
(N=116)
Mean
VA
Change
from
Baseline
Cohort by Cumulative Visits with Edema (CRT≥250µm) at week 52 or 104
VA Improvement at Week 104
P-value for C1 vs C4 at 12m = 0.013
P-value for C1 vs C4 at 24m = 0.003

Clinically-relevant baseline differences in patients with persistent
edema
Cumulative Number of Visits with CRT ≥250 µm
During Year 1
Cohort 1:
≤3 visits
Cohort 2:
4-7 visits
Cohort 3:
8-11 visits
Cohort 4:
≥12 visits
P-value
N 85 90 70 122
Mean age, years 61.3 62.6 63.9 63.3 0.451
Male, N (%) 40 (47.1%) 51 (56.7%) 42 (60.0%) 74 (60.7%) 0.232
Mean baseline VA, ETDRS
letters
64.7 62.4 60.4 63.1 0.223
Mean baseline CRT, µm 339 415 420 439 <0.001
Prior DME treatment, N (%) 41 (48.2%) 57 (63.3%) 48 (68.5%) 77 (63.1%) 0.048
Source of the data is the DRCR.net, but the analyses, content and conclusion presented are solely the responsibility of the authors and have not been reviewed or approved by
DRCR.net
CRT: Central Retinal Thickness; ETDRS: Early Treatment Diabetic Retinopathy Study; VA: Visual Acuity.

Adjusting for potential confounders, eyes with the most persistent
edema were estimated to gain significantly fewer letters
*Coefficient from linear regression also adjusted for age, baseline
VA, baseline CRT, prior DME treatment before study entry (Y/N), cumulative # RAN inj, and cumulative # laser proc

Adjusting for potential confounders, eyes with the most persistent
edema were also significantly less likely to gain ≥10 letters
*Odds ratio from logistic regression also adjusted for age, baseline VA, baseline CRT, prior DME treatment before study entry (Y/N), cumulative # RAN inj, and cumulative # laser proc

Summary: Protocol I persistence of Edema
• In this post-hoc analysis of DRCR.net Protocol I data, one-third of patients experienced
persistent edema during the first year (≥12 visits with CRT≥250µm) after initiation of
ranibizumab treatment
For the majority of these patients, edema persisted (≥11 visits) through Year 2
• In unadjusted analyses, gains in vision improvement were lower for eyes with persistent
edema at weeks 52 and 104, though there was greater variability in response over time
• Adjusting for potential confounders, including baseline BCVA, a significant negative
association between persistent edema and long-term BCVA improvement at weeks 52,
104, and 156 remained
BCVA: Best Corrected Visual Acuity; CRT: Central Retinal Thickness; VA: Visual Acuity.

Conclusions: Post-hoc analysis of Protocol I
• This analysis provides new evidence demonstrating an association between anatomic
and functional response
to ranibizumab
• In eyes with persistent edema
– final visual acuity limited
– early consideration of additional disease management strategies may be appropriate to maximize
potential vision benefit

Are the findings replicated in real life?
The UK DR EMR Users Group Report 1
Key features of the EMR
• Medisoft
• VA record for each eye for each visit
– Specifically records if VA level can be attributed to DR
• Structured feature based grading of diabetic retinopathy
– By eye, by DR severity scale, DME features
• DR scale automatically computed
• All interventions (laser focal, PRP, IVT, phako, vitrectomy) by eye and by date
– Intravitreal drug administration by eye, by drug, injection location
DME: Diabetic Macular Edema; DR: Diabetic Retinopathy; EMR: Electronic Medical Records; IVT: Intravitreal; PRP: Panretinal Photocoagulation; VA: Visual Acuity.
13. Egan C, Zhu H, Lee A, et al. The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema. Br J Ophthalmol .
2017;101(1):75–80.

Study Design
• 19 centres
• Data extract Nov 2014 (one year after NICE approval of Ranibizumab for DME)
• VA (not BCVA but best measured VA ) one third were Snellen and
two thirds ETDRS
BCVA: Best Corrected Visual Acuity; DME: Diabetic Macular Edema; DR: Diabetic Retinopathy; EMR: Electronic Medical Records; ETDRS: Early Treatment Diabetic Retinopathy Study; NICE: National Institute for Health and Care Excellence; VA: Visual Acuity.
2017;101(1):75–80.

• Data from 3,103 eyes treated with Ranibizumab
• Mean VA (letters)
– Baseline - 51.1 (SD=19.3)
– Year 1 - 54.2 (SD: 18.6)
– Year 2 - 52.5 (SD: 19.4)
• Mean visual gain - 5 letters
• Proportion of eyes with VA ≥ 72 letters
– Baseline - 25%
– Year 1 - 33%
– Year 2 – 24%
• Eyes followed for at ≥ 6 months received
– a mean of 3.3 injections
– 6.9 outpatient visits on average
DR: Diabetic Retinopathy; EMR: Electronic Medical Records; VA: Visual Acuity.
2017;101(1):75–80.

Visual Acuity Results
VA (mean + SD) vs months
since last injection
Number of eyes treated against
months from first injection of
ranibizumab
DR: Diabetic Retinopathy; EMR: Electronic Medical Records; VA: Visual Acuity.
2017;101(1):75–80.

Visual acuity change (letters) stratified by baseline
VA in treatment naïve eyes
ETDRS: Early Treatment Diabetic Retinopathy Study; VA: Visual Acuity.
2017;101(1):75–80.

Change in VA from baseline
Change in VA
from baseline
Lost 30
or more
-15 to -29 -1 to -14 0 to +14 +15- +29 > +30
Eyes (N=2,292),
n (%)
30
(1.3%)
0
490
(21.4%)
1375 (60%)
318
(13.9%)
79
(3.4%)
Injections,
n (SD)
4.6 (2.6) 0 5.4 (2.8) 5.3 (2.9) 6.1 (3.6) 5.8 (3.3)
VA: Visual Acuity.
2017;101(1):75–80.

Real life outcomes
• Treatment naïve better seeing eye
• Proportion VA 20/40 or better improved at one year but had fallen to just below
baseline by year 2
• Baseline 25%
• Year 1 33%
• Year 2 24%
VA: Visual Acuity.
2017;101(1):75–80.

Association of injection no. and VA difference between last and first
injection to baseline VA in treatment naïve eyes
Baseline visual acuity did not influence
the number of treatments
Baseline visual acuity influenced change: the worse
the VA at baseline the greater the improvement
VA: Visual Acuity.
2017;101(1):75–80.

EMR summary
• Eyes with good starting VA (70-100 letters) at baseline maintained
good mean VA, showed a slight negative gain (-2 letters at 18 months), but maintained
good vision
• Eyes with worse starting VA, achieved a greater gain but average final VA was 5 letters
(half that observed in the pivotal trials)
• 33% of patients achieved > 20/40 vs 62% in RISE & RIDE
• VA achieved at 6 months was stable at 18 m except in the group with worst VA at
baseline
EMR: Electronic Medical Records; VA: Visual Acuity.
2017;101(1):75–80.

Study VA inclusion criteria have changed over time and has potential
to influence outcome?
Study RESOLVE14 RIDE & RISE15 DA VINCI16 VIVID & VISTA17 Protocol T10
Drug Ranibizumab Ranibizumab Aflibercept Aflibercept
Ranibizumab,
Aflibercept,
Bevacizumab*
Recruitment period Jan 2006 –
June 2007 –
Jan 2009
Nov 2008 –?
May 2011 – June
2013
Aug 2012 –
Aug 2013
VA range at enrolment 20/40 – 20/160 20/40 – 20/320 20/40 - 20/320 20/40 - 20/320 20/32 - 20/320
Mean age (yrs) 63.0 61.8–63.5 60.7-64.0 61.7 – 64.2 56-62.0
Diabetes duration (yrs)
14.2
(0.7–46.0)
14.5 – 16.3 ? 14.1 – 17.6 15-17
Mean VA at baseline:
letters
60.2 54.7 – 57.5 57.6 – 59.9 58.9 – 60.8 55.8–56.9
Proportion with VA
better than 20/40
17 – 25 % 17 – 25 % NI NI > 50 %
*Not licensed for ophthalmological use. VA, visual acuity.
14. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33(11):2399-405.
15. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmol 2012;119(4):789–801.
16. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmol 2011;118(9):1819–26.
17. Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247–54.

Disorganisation of Retinal Inner Layers (DRIL) SD-OCT
Increasing duration of DME results in worsening of the inner retinal
morphology
Chronic: Retinal layer
boundaries can only be
partially identified
Non chronic: Retinal layer
boundaries can
be identified
DRIL: Disorganisation of Retinal Inner Layers; GCL: Ganglion Cell Layer; INL: Inner Nuclear Layer; IPL: Inner Plexiform Layer; ONL: Outer Nuclear Layer; OPL: Outer Plexiform Layer; SD-OCT: Spectral Domain Optical Coherence tomography.
Images provided courtesy of Dr. Sun

Reversibility of DRIL and Associated Change in VA
Improving DRIL improved function
• 66% (N=69) of eyes with baseline DRIL had DRIL improvement at 8m
• When DRIL decreased >50µm at 4m, VA was stable or increased
in 97% (N=29) of eyes at 8m
• When DRIL decreased >250µm over 4m, no eyes had VA decline
>1 line, but 78% had VA increase >1 line at 8m
Baseline
VA 20/50
4 Months
VA 20/32
8 Months
VA 20/25
DRIL: Disorganisation of Retinal Inner Layers; VA: Visual Acuity.
Images provided courtesy of Dr. Sun.

Initial treatment considerations
• Baseline visual acuity:
– Influences final visual acuity
– When stratified by baseline VA there are differential
outcomes to treatments
• Retinal morphology:2
– Also influence final visual acuity
– DRIL is a surrogate for chronicity
DRIL: Disorganisation of Retinal Inner Layers; VA: Visual Acuity.
2017;101(1):75–80.

Questions in real life
• How to decide on which treatment for which patient?
• Are there safety concerns with DME treatments?
DME: Diabetic Macular Edema.

Association of Diabetic Macular Edema and Proliferative Diabetic
Retinopathy With CVD
• Design
– 7604 individuals were included from 8 prospective population-based studies with data on photographic-
based DR grading, follow-up visits, and well-defined incident CVD end point
• Results
– Among 7604 patients with type 2 diabetes, the prevalence of DME was 4.6% and of PDR 7.4%.
– After a mean follow-up of 5.9 years (range, 3.2-10.1 years),
• 1203 CVD events
• Including 916 coronary heart disease cases,
• Patients with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95% CI, 1.49-3.67)
compared with those without DME or PDR.
• Conclusions and Relevance
– Patients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests they
should be followed up more closely to prevent CVD
CI: Confidence Interval; CVD: Cardiovascular Disease; DME: Diabetic Macular Edema; DR: Diabetic Retinopathy; IRR: Incidence Rate Ratio; PDR: Proliferative Diabetic Retinopathy.
18. Xie J, Ikram MK, Cotch MF, et al. Association of Diabetic Macular Edema and Proliferative Diabetic Retinopathy With Cardiovascular Disease: A Systematic Review and Meta-analysis. JAMA Ophthalmol 2017;135(6):586–93.

When we face a type 2
diabetic patient with DME
how should we proceed?

ETDRS: Early Treatment Diabetic Retinopathy Study; HbA1c: Glycated Gemoglobin; ME: Macular Edema; OCT: Optical Coherence Tomography; VA: Visual Acuity; VEGF: Vascular Endothelial Growth Factor.
19. Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica 2017;237(4):185-222.
20. International Council of Ophthalmology. Guidelines for Diabetic Eye Care 2017. Available from: http://www.icoph.org/downloads/ICOGuidelinesforDiabeticEyeCare.pdf. Accessed on July 25, 2020.
21. Ozurdex. PI.
22. Iluvien. Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/3061. Accessed on July 25, 2020.
The following should be evaluated prior to therapy initiation:
glucose control (HbA1c), diabetic complications and co-morbidities, VA, biomicroscopy, OCT+/-FA , +/-OCTA19
Non-central involved ME Central-involved ME
If no VA loss or <5 letter
decrease; observation19,20
PPV in patients with no
posterior vitreous detachment19
History of major CV event
Corticosteroidsa19* ANTI-VEGF19
Laser‡20
Pseudophakic eyes
Corticosteroidsa*19
No history of major CV event
Phakic eyes
ANTI-VEGF
(plus laser if needed)19,20
CORTICOSTEROIDS in
patients insufficiently
responsive*19,21
CORTICOSTEROIDSa*
in patients deemed unsuitable for anti-
VEGF21 or patients who are not willing
to come for monthly injections (and/or
monitoring) in the first 6 months of
therapy19**
aCORTICOSTEROIDS of which DEX DDS
is recommended first19
Tractional ME†
ME
ANTI-VEGF19
Corticosteroidsa*19
FLUOCINOLONE*
in nonsteroid responders with
chronic ME that is not responsive
to other treatments19,22
*Not recommended if pre-existing or uncontrolled advance glaucoma is present; †anterior-posterior traction; ‡Focal
laser; **IOP needs to be monitored
Treatment algorithm proposed by authors; to be adapted according to local country guidelines.

21. Ozurdex. PI.
Laser‡20
Pseudophakic eyes
Corticosteroidsa*19
Phakic eyes
ANTI-VEGF
CORTICOSTEROIDS in
responsivea*19,21
CORTICOSTEROIDSa*
therapy19**
Tractional ME†
ME
ANTI-VEGF19
Corticosteroidsa*19
FLUOCINOLONE*
Patient group not outlined in current
guidelines—suggested therapy by authors.
Country guidelines to be checked for this
setting
Corticosteroids*
Vitrectomised
eyes

21. Ozurdex. PI.
Laser‡20
Pseudophakic eyes
Corticosteroidsa*19
Phakic eyes
ANTI-VEGF
CORTICOSTEROIDS in
responsivea*19,21
CORTICOSTEROIDSa*
therapy19**
Tractional ME†
ME
ANTI-VEGF19
Corticosteroidsa*19
FLUOCINOLONE*
Corticosteroids*
Vitrectomised
eyes

Patient case
• To be incorporated
BE: Both Eyes; IOP: Intraocular Pressure; LE: Left Eye; RE: Right Eye; VA: Visual Acuity.
Patient case provided by authors.

21. OzurdexPI.
Laser‡20
Pseudophakic eyes
Corticosteroidsa*19
Phakic eyes
ANTI-VEGF
CORTICOSTEROIDS in
responsivea*19,21
CORTICOSTEROIDSa*
therapy19**
Tractional ME†
ME
ANTI-VEGF19
Corticosteroidsa*19
FLUOCINOLONE*
Corticosteroids*
Vitrectomised
eyes

Patient case
• To be incorporated

Anti-VEGF for management of DME – Key Points
Efficacy
• Effective and fast acting23–25
• Target one mediator, anti-VEGF24,25
• Real life data differs from study data - Outcome depends on # of injections and baseline VA 24–29
• Not all patients respond the same - Appr 20–40% of patients insufficient responders*26,28,15
• Some patients become resistant or develop rebound edema30
Safety
• Caution should be exercised when treating patients with a recent (3–6 months) CV event†24,25
• There might be an increased risk of arterial thromboembolic events following intravitreal use of anti-
VEGFs24,25,27,15
• Risk for compliance/capacity issues27,31
CV: Cardiovascular; DME: Diabetic Macular Edema; VEGF: Vascular Endothelial Growth Factor; VA: Visual Acuity.
†Cardiovascular disease means recent (3–6 months) myocardial infarction, stroke, or other thromboembolic recent events
*Insufficiently responsive if <5 letter VA improvement and/or <10% decrease in central retinal thickness
23. Boyer DS, Hopkins JJ, Sorof J, et al. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrin Metab. 2013;4(6):151–169.
24. Lucentis. Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/307/smpc#:~:text=Ranibizumab%20is%20a%20humanised%20recombinant,%2D1%20and%20VEGFR%2D2. Accessed on July 25, 2020.
25. Eylea. Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2879/smpc#:~:text=Eylea%2040%20mg%2FmL%20solution,microlitres%20containing%202%20mg%20aflibercept. Accessed on July 25, 2020.
26. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Am J Ophthalmol. 2016;172:72–79.
27. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013–2022.
28. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130(9):1153–1161.
29. Campbell J, Cole AL, Almony A, et al. Real World Vision Outcomes in DME Treated with Anti-VEGF Injections - An Analysis of EMR Data From a Large Health System. Investigative Ophthalmology & Visual Science . 2014;55(13):3065.
15. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmol 2012;119(4):789–801.
30. Agarwal A, Sarwar S, Sepah YJ, et al. What have we learnt about the management of diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era? Curr Opin Ophthalmol. 2015;26(3):177–83.
31. Sivaprasad S and Oyetunde S. Impact of injection therapy on retinal patients with diabetic macular edema or retinal vein occlusion. Clinical Ophthalmology. 2016;10:939–946.

Not all patients with DME are optimal responders DRCR Protocol I
Sub-analysis
• Sub-analysis to determine if factors may predict anti-VEGF treatment success or failure
• Study eyes were differentiated into 1 of 4 categories based on whether they had at
least a 20% reduction from baseline CSF thickness at the 16-week visit
CATEGORIZATION OF OCT THICKNESS IMPROVEMENT OF AT LEAST 20%
(1-STEP REDUCTION OF LOG) FROM BASELINE (N=288)
Early and
Consistent
Early but
Inconsistent
Slow and Variable Non-Responder
Improved at the 16-
week study visit and
was sustained at the
32-week and 1-year
study visits
Improved at the 16-
week study visit but
not at both the 32-
week and 1-year
study visits
Did not improve at
the 16-week study
visit but did improve
at the 32-week and/or
1-year study visits
Did not improve at
the 16-week, 32-
week, or 1-year study
visit
n=143 (49.7%) n=43 (14.9%) n=36 (12.5%) n=66 (25.9%)
CSF: Central Subfield; DME: Diabetic Macular Edema; DRCR: Diabetic Retinopathy Clinical Research; VEGF: Vascular Endothelial Growth Factor.
28. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130(9):1153–1161.

Patient case
• Dr to incorporate a patient case from his clinical practice of Ozurdex in non responder
– OCT image (pre & post)
– FFA image (Pre & post)
– severe chronic edema the patient has, with significant leakage on FA and with non perfusion in the
macula, intraretinal lipids, confirmed by OCT to have a very thickened retina

What to do if a patient is a high risk patient/ or a patient with a
recent CVD event?
• DM patients have higher incidence of micro and macro vascular disease
• Anti-VEGF labels carry cautions/theoretical cautions about usage in patients
with recent vascular events
• What is the totality of the evidence?
CVD: Cardiovascular Disease; DM: Diabetes Mellitus; VEGF: Vascular Endothelial Growth Factor.
32. Zarbin MA, Dunger-Baldauf C, Haskova Z, et al. Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials. JAMA Ophthalmology. 2017;135(5):424–431.
25. Eylea. Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/2879/smpc#:~:text=Eylea%2040%20mg%2FmL%20solution,microlitres%20containing%202%20mg%20aflibercept. Accessed on July 25, 2020.
24. Lucentis. Summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/307/smpc#:~:text=Ranibizumab%20is%20a%20humanised%20recombinant,%2D1%20and%20VEGFR%2D2. Accessed on July 25, 2020.

Protocol T pre-specified APTC* Adverse Events through 2 Years10
APTC: Anti-Platelet Trialists Collaboration; MI: Myocardial Infarction.
33. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ.
1994;308(6921):81-106.
% of pts with at least
one event
Aflibercept
(N = 203)
Bevacizumab‡
(N = 193)
Ranibizumab
(N = 193)
Global
P-Value
Non-fatal MI 3% 2% 2%
Non-fatal stroke <1% 3% 3%
Vascular death <1% 2% 4%
Any APTC Event 5% 6% 9% 0.047†
*Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.33
‡Not licensed for ophthalmological use.
†Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = 0.34, aflibercept-ranibizumab: P = 0.047, bevacizumab-ranibizumab: P = 0.20.
Global P-value adjusting for gender, age at baseline, Hemoglobin A1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior myocardial infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status: P
= 0.09.
The table details the values of study participants with no MI or stroke prior to baseline to those with MI or stroke prior to baseline.

In the pivotal trials patients with recent CVA & MI were excluded
CVA: Cerebrovascular Accident; MI: Myocardial Infarction.
34. Avery RL and Gordon GM. Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema: A Systematic Review and Meta-analysis. JAMA Ophthalmol. 2016;134(1):21–29.
No CVA or MI within
last 3 months
No CVA or MI within
Last 6 months
No CVA or MI in 866/1767 (49%)
of enrolled patients (RESTORE,
RELATION, REVEAL)

Systemic Safety of Prolonged Monthly Anti-VEGF Therapy for Diabetic
Macular Edema1
CI: Confidence Interval; HR: Hazard Ratio; OR: Ods Ratio. VEGF: Vascular Endothelial Growth Factor.
34. Avery RL and Gordon GM. Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema: A Systematic Review and Meta-analysis. JAMA Ophthalmol. 2016;134(1):21–29.
all-cause mortality:
HR 0.3mg R vs control = 1.72 (0.50, 5.88)
HR 0.5mg R vs control = 2.19 (0.85, 5.61)

Patient case
• Medical History: stroke past year
• Pseudophakic
• Naïve
• Moderate-Severe NPDR + DME

BCVA: Best Corrected Visual Acuity; BSL: Baseline; DEX: Dexamethasone; ITT: Intention To Treat. VA: Visual Acuity.
35. Callanan DG, Gupta S, Boyer DS, et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013;120(9):1843–51.
36. Boyer DS, Yoon YH, Jr RB, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121(10):1904–14.
37. Soare S, Hajjar C, Parrat E, et al. Multicenter OZurdex Assessment foR diabeTic macular edema :MOZART study. Investigative Ophthalmology & Visual Science. 2013:54:2387.
38. Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31(5):915–23.
MEAD >15 letter gain36
Dexamethasone 0.35mg, 0.7mg significantly better than sham, 3 y
CHAMPLAIN38
By week 8 30% improvement of 2-line in VA
MOZART37
Better VA results in naïve patients
PLACID35
Significant difference seen at mo. 1 & 9
22.2
18.4*
12.0
23.3*
15.9
10.9
21.9*
19.3*
12.4
0.0
5.0
10.0
15.0
20.0
25.0
30.0
DEX 700 DEX 350 Sham
Patients
with
Improved
BCVA
(%)
ITT BSL Pseudophakic BSL Phakic
5.4
1.6
6.7 6.7
0
1
2
3
4
5
6
7
8
9
10
2 Months 6 Months
Letters
gained
Steroid Implants: BCVA Letter Gain in MOZART study
All patients
Treatment näive

Mean BCVA change from baseline based on baseline lens status –
MEAD
BCVA: Best Corrected Visual Acuity; DEX: Dexamethasone.
-2
0
2
4
6
8
10
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Mean
Change
From
Baseline
BCVA
(Letters)
Month
DEX Implant 0.7 mg (n = 86)
DEX Implant 0.35 mg (n = 88)
Sham (n = 101)
Pseudophakic
Total
0
5
10
0 3 6 9 12 15 18 21 24 27 30 33 36 39
DEX 700 (n=351)
DEX 350 (n=347)
Sham (n=350)
Mean
Change
from
Baseline
BCVA
(Letters)
Month

IOP Increase at scheduled visits after study treatment
DEX: Dexamethasone; IOP: Intraocular Pressure.
39. Maturi RK, Pollack A, Uy HS, et al. INTRAOCULAR PRESSURE IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE INTRAVITREAL IMPLANT IN THE 3-YEAR MEAD STUDY. Retina 2016;36(6):1143-52..
% of pts with an increase in IOP of >10 mmHg

Ocular adverse events in the study eye reported in ≥2% of patients in
any treatment group
DEX: Dexamethasone.

Patients Who Underwent Cataract Surgery Eventually Gained the
Same Visual Benefit as Pseudophakic Patients
AE: Adverse Event; BCVA: Best Corrected Visual Acuity; DEX: Dexamethasone; ETDRS: Early Treatment Diabetic Retinopathy Study; ITT: Intention To Treat.
Results analyzed in the ITT population with an area-under-the-curve approach
Numbers in parentheses indicate number of patients
5.3
-9.7
4.3
6.7 6.5
4.8
-7.0
4.7
7.1
5.9
-10
-5
0
5
10
Mean
average
change
in
BCVA
from
baseline
(ETDRS
letters)
DEX Implant 0.7 mg DEX Implant 0.35 mg
(176) (159)
(132) (118)
(142) (123) (73) (63) (86) (88)
Phakic patients with cataract adverse event (AE)
Baseline
pseudophakic
patients
>12 months
follow-up
Baseline to
AE
AE to cataract
surgery
After cataract surgery

Patients Who Underwent Cataract Surgery Eventually Gained the
Same Visual Benefit as Pseudophakic Patients
Results analyzed in the ITT population with an area-under-the-curve approach
Numbers in parentheses indicate number of patients
5.3
-9.7
4.3
6.7 6.5
4.8
-7.0
4.7
7.1
5.9
-10
-5
0
5
10
Mean
average
change
in
BCVA
from
baseline
(ETDRS
letters)
DEX Implant 0.7 mg DEX Implant 0.35 mg
(176) (159)
(132) (118)
(142) (123) (73) (63) (86) (88)
Phakic patients with cataract adverse event (AE)
Baseline
pseudophakic
patients
>12 months
follow-up
Baseline to
AE
AE to cataract
surgery
After cataract surgery
AE: Adverse Event; BCVA: Best Corrected Visual Acuity; DEX: Dexamethasone; ETDRS: Early Treatment Diabetic Retinopathy Study; ITT: Intention To Treat.

Are the findings replicated
in Real Life?

Meta analysis of Real life studies Dex Implant vs Anti-VEGF
3,859 patients treated for recalcitrant DME with ≥6 prior treatments
of intravitreal anti-VEGF: Favors Dex Implant
CI: Confidence Interval; DEX: Dexamethasone; DME: Diabetic Macular Edema; VEGF: Vascular Endothelial Growth Factor.
40. Khan Z, Kuriakose RK, Khan M, et al. Efficacy of the Intravitreal Sustained-Release Dexamethasone Implant for Diabetic Macular Edema Refractory to Anti-Vascular Endothelial Growth Factor Therapy: Meta-Analysis and Clinical Implications. Ophthalmic Surg Lasers Imaging
Retina. 2017;48(2):160–166.

The study authors concluded that treatment with Ozurdex® is
associated with a significant mean improvement in visual acuity of
four lines (20 ETDRS letters) in cases of DME refractory to anti-VEGF
therapy. Clinicians should be aware of patients who are responding
inferiorly to anti-VEGF and consider corticosteroid therapy to improve
visual acuity outcomes
DME: Diabetic Macular Edema; ETDRS: Early Treatment Diabetic Retinopathy Study; VEGF: Vascular Endothelial Growth Factor.
40. Khan Z, Kuriakose RK, Khan M, et al. Efficacy of the Intravitreal Sustained-Release Dexamethasone Implant for Diabetic Macular Edema Refractory to Anti-Vascular Endothelial Growth Factor Therapy: Meta-Analysis and Clinical Implications. Ophthalmic Surg Lasers Imaging
Retina. 2017;48(2):160–166.

DEX Implant in Patients with Naïve or Refractory Diffuse DME
†Suitable naïve patients were included in the study to investigate the effect of early treatment with Dex Implant.
DEX: Dexamethasone; DME: Diabetic Macular Edema; ETDRS: Early Treatment Diabetic Retinopathy Study; VA: Visual Acuity.
Ozurdex® is indicated for the treatment of adult patients with visual impairment due to DME who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy.
41. Escobar-Barranco JJ, Pina-Marín B and Fernández-Bonet M. Dexamethasone Implants in Patients with Naïve or Refractory Diffuse Diabetic Macular Edema. Ophthalmologica. 2015;233(3–4):176–85.
*p<0.001 vs. baseline
*
Baseline 3 weeks 2 months 3 months 4 months 6 months
8
6
4
0
2
10
12
14
16
18
*
*
*
*
*
*
*
*
*
Increase
in
ETDRS
letters
over
baseline
[mean
(min/max)]
Naive
Refractory
Time
• 76 patients with diffuse DME (40 refractory and 36 naïve†)
• VA improved significantly (p<0.001) at every visit in both groups
• Average gain in VA from baseline at month 6
• Naïve: 12 letters, median re-injection time 5 months
• Refractory: 8 letters, median re-injection time 4 months

The BEVORDEX Study
• Head-to-head comparison of DEX and bevacizumab*
• Prospective, multicenter, randomized, single-masked clinical trial
• 88 eyes of 61 pts with center-involving DME
bevacizumab n = 42; DEX n= 46
*Not licensed for ophthalmological use.
DEX: Dexamethasone; DME: Diabetic Macular Edema; ODX: Ozurdex; VA: Visual Acuity.
42. Gillies MC, Lim LL, Campain A, et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study. Ophthalmology. 2014;121(12):2473–81.
43. Fraser-Bell S, Lim LL, Campain A, et al. Bevacizumab or Dexamethasone Implants for DME: 2-year Results (The BEVORDEX Study).Ophthalmology 2016;123(6):1399–401.
P-value=0.77

Change in VA from baseline I pseudophakic eyes
*Not licensed for ophthalmological use.
CI: Confidence Interval; DEX: Dexamethasone; VA: Visual Acuity.
Mean VA improvement with 95% CI:
Bevacizumab* = 7.7 [3.03-14.8]
DEX implant = 8.9 [2.0-13.4]
(P-value=0.77)

Number of treatments received
*Not licensed for ophthalmological use. DEX, dexamethasone.
Please note that not all countries will be able to use a made-up graph.
42. Gillies MC, Lim LL, Campain A, et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study. Ophthalmology. 2014;121(12):2473–81.
44. Mehta H, Fraser-Bel S, Nguyen V, et al. The Interval between Treatments of Bevacizumab and Dexamethasone Implants for Diabetic Macular Edema Increased over Time in the BEVORDEX Trial. Ophthalmology Retina. 2017;1-4.
Gillies 20141
(in Year 1)
Mean
number
of
treatments
Fraser-Bell 20162
(in Year 1)
Fraser-Bell 20162
(in Year 2)
2.7 2.8
2.2
5.6
8.6
9.1
4.8
14.6
0
2
4
6
8
10
12
14
16
Dex Implant
Bevacizumab*
Adapted from
Mehta 201744
(in total across 2 years)
Adapted from
Gillies 201442
(in Year 1)
Adapted from
Fraser Bell 201643
(in Year 1)
Adapted from
Fraser Bell 201643
(in Year 2)

Ozurdex – Key Points
Efficacy
• Targets multiple inflammatory mediators, not only VEGF36,21
• Good efficacy, in both short and long duration DME patients45,41, 47, 36, 21
• Fast acting and long-duration45,41,36,21
• Patient suitability (in accordance with licence)41,47,36,21
• Low injection regime, less burden for doctors, patients and payers45,41,36
• Patients may respond after unresponsiveness to anti-VEGF therapies45,46
• Patients previously treated with laser therapy or anti-VEGF therapies can be treated
with Ozurdex®45,41,47,21
Side effects
• Minimal or no systemic side-effects (limited systemic circulation)41
• Increase of IOP (normally transient) and Cataract45,41,36,21
DME: Diabetic Macular Edema; IOP: Intraocular Pressure; VEGF: Vascular Endothelial Growth Factor.
45. Udaondo P. One-Year Results of Intravitreal Dexamethasone Implant in Drug-naïve Patients with Diabetic Macular Edema. Poster PO213. Presented at AAO. New Orleans, USA. 2013.
46. Medeiros MD, Postorino M, Navarro R, et al. Dexamethasone Intravitreal Implant for Treatment of Patients with Persistent Diabetic Macular Edema. Ophthalmologica. 2014;231(3):141–146.
47. Guigou S, Hajjar C, Parrat E, et al. [Multicenter Ozurdex® assessment for diabetic macular edema: MOZART study]. J Fr Ophtalmol . 2014;37(6):480-5.
21. Ozurdex. PI.

Factors to consider when choosing treatment
• Predictors of long-term visual acuity response to anti-VEGF therapy:
A post-hoc analysis of Protocol I data.
CRT: Central Retinal Thickness; VA: Visual Acuity; VEGF: Vascular Endothelial Growth Factor.
48. Dugel PU. Long-term response to anti-VEGF therapy for diabetic macular edema can be predicted after 3 injections: an analysis of Protocol I data. Paper presented at: American Academy of Ophthalmology .2015 Annual Meeting. Retina Subspecialty Day. 2015;Las Vegas, NV. 20.
39.7%
23.2%
37.1%
< 5 Letters
Improvement
5-9 Letters
Improvement
≥ 10 Letters
Improvement
RAN + Deferred or Prompt Laser
Sample size at baseline 375
VA observed at 12 weeks 340
CRT observed at 12 weeks 335
Stratification into
3 cohorts at 12w
35.0%
65.0%
<20% Improvement in
CRT (N=118)
≥20% Improvement in
CRT (N=217)

Eyes with <5 letter gain after 3 injections showed limited additional
improvement for the study duration (3 years)
VA: Visual Acuity.
26. Dugel pu et al. clinical ophthalmology 2016
-0.3
2.8 3.0
6.9
8.2 8.2
15.2
16.5
13.8
-5
0
5
10
15
20
BL 12 16 20 24 28 32 36 40 44 48 52 . .. … 68 . .. … 84 . .. … ….104 . ..
…
120 . ..
…
136 . . . .. . … . ….156
VA
Change
from
Baseline
p<0.001
Weeks
≥10 letters
at 12w (N=126)
5-9 letters
at 12w (N=79)
<5 letters
at 12w (N=135)

53.3% of patients did not experience additional gains with anti-VEGF
treatment
VEGF: Vascular Endothelial Growth Factor.
26 Dugel pu et al. clinical ophthalmology 2016
Eyes with <5 letter improvement at 12 weeks, n=135
11.9%
23.0% 22.2%
28.9%
25.2%
28.9% 25.9% 17.8%
100%
63.0%
48.1% 51.9% 53.3%
0%
20%
40%
60%
80%
100%
12w 24w 52w 104w 156w
Proportion
of
Eyes
≥10 letters
Improvement
5-9 letters
Improvement
<5 letters
Improvement

Amongst modest gainers (5-9 letters) of vision, a substantial
proportion of eyes experienced <5 letters improvement by study end
*Width of bubbles represents relative size of sample
Error bars show 95% confidence intervals
Dugel pu et al. clinical ophthalmology 2016
Eyes with 5-9 letter improvement at 12 weeks, n=79
35.4%
44.3% 48.1% 48.1%
38.0%
25.3%
25.3% 24.1%
26.6% 30.4% 26.6% 27.8%
0%
20%
40%
60%
80%
100%
24w 52w 104w 156w
Proportion
of
Eyes
≥10 Letters
Improvement
5-9 Letters
Improvement
<5 Letters
Improvement

Eyes categorized by early VA response differed in several baseline
characteristics
CRT: Central Retinal Thickness; DME: Diabetic Macular Edema; VA: Visual Acuity.
VA change from baseline at 12 weeks
<5 letter
improvement
5-9 letter
improvement
≥10 letter
improvement
P-value
Study eyes, n (%) 135 (39.7%) 79 (23.2%) 126 (37.1%)
Mean age, years 64.3 61.9 61.7 0.036
Male gender (%) 57.8% 48.1% 59.5% 0.775
Mean baseline VA, letters 65.2 64.94 58.8 <0.001
Mean baseline CRT, μm 379 384 438 <0.001
Prior DME treatment, % 63.7% 62.0% 58.7% 0.410

Similar findings are seen in the subgroup of eyes with VA <69 letters
at baseline
VA: Visual Acuity.
49. Augustin, et al. Predictive factors for improved visual acuity in patients treated with anti-VEGF for diabetic macular edema (DME). Presented at Club Jules Gonin Meeting. Bordeaux, France. July 6-9, 2016..
-0.9
4.3 3.8
6.9
9.4 9.9
16.0
18.0 15.6
-5
0
5
10
15
20
BL
12
16
20
24
28
32
36
40
44
48
52
.
..
…
68
.
..
…
84
.
..
…
….
104
.
..
…
120
.
..
…
136
.
.
.
..
.
…
.
….
156
VA
Change
from
Baseline
Weeks
<5 letters at 12w
(n=68)
5-9 letters at 12w
(n=45)
≥10 letters at 12w
(n=99)
p<0.001

Eyes with <20% CRT improvement at week 12 had lower mean VA
change from baseline over the study duration
CRT: Central Retinal Thickness; VA: Visual Acuity.
49. Augustin, et al. Predictive factors for improved visual acuity in patients treated with anti-VEGF for diabetic macular edema (DME). Presented at Club Jules Gonin Meeting. Bordeaux, France. July 6-9, 2016.
3.6
4.8
4.0
9.2
11.5
10.4
0
2
4
6
8
10
12
14
Mean
VA
Change
from
baseline
Week
<20% proportional change in CRT at 12w (n=118) ≥20% proportional change in CRT at 12w (n=217)
p<0.001

After controlling for potential confounders*, significant association
remained between early and late VA response
• Estimate of association between proportional OCT improvement at 12 weeks
and long-term BVA improvement attenuated (not statistically significant)
CRT: Central Retinal Thickness; OCT: Optical Coherence Tomography;VA: Visual Acuity.
Multivariate Linear Regression* on
VA Change from Baseline
N=335
At Week 52 At Week 156
Parameter Estimate P-Value Estimate P-Value
VA change from baseline
at Week 12
0.72 <0.001 0.56 <0.001
≥20% improvement in CRT
at Week 12
1.59 0.205 1.88 0.268
*Covariates include: Age, Gender, Baseline VA, Baseline CRT, Change in VA at week 12, Change in CRT at week 12 (≥20% vs <20%), Cumulative # ranibizumab injections at week
52/156, Cumulative # laser procedures at week 52/156, Prior DME Treatment at baseline (Yes/No)

EARLY study summary
• Post-hoc analysis of DRCRnet Protocol I data showed that VA response after 3 anti-VEGF
injections (at 12 weeks) was statistically significantly associated with long-term VA
response
• Statistical Significant association between early and long-term VA response remained
even after adjusting for baseline characteristics
• After adjusting for confounders, significant variability in long-term VA response by early
CRT response was seen; the association was attenuated and no longer statistically
significant
CRT: Central Retinal Thickness; OCT: Optical Coherence Tomography;VA: Visual Acuity.

Patient case
• Dr to incorporate a patient case from his clinical practice of
• “multiple hemorrhages and cotton wool spots, neovascularization superior nasal to disc
• Neovascularization of the disc
• Management with Ozurdex
– OCT image (pre & post)
– FFA image (Pre & post)

Conclusion 1: Tailoring therapy for best outcomes
• Multi-targeted treatment paradigms, aiming at multiple pathways19,20
• Choosing the right therapy for the right patient has the potential to increase responder
rates45,46
• Individualise therapy – Not all patients respond identically to treatment
Protocol I sub-analyses shows that a decision on responder status can
be made at 12 weeks26
• In suboptimaI or non-responders consider switching to alternative therapy41,40,21
• Reduce treatment burden for healthcare system and patients45,41,36
• Work to detect subclinical DME changes, allowing better management
of treatment initiation, cessation and retreatment7
45. Udaondo P. One-Year Results of Intravitreal Dexamethasone Implant in Drug-naïve Patients with Diabetic Macular Edema. Poster PO213. Presented at AAO. New Orleans, USA. 2013.
46. Medeiros MD, Postorino M, Navarro R, et al. Dexamethasone IntravitrealImplant for Treatmentof Patientswith Persistent Diabetic MacularEdema. Ophthalmologica.2014;231(3):141–146.
26. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Am J Ophthalmol. 2016;172:72–79.
40. Khan Z, Kuriakose RK, Khan M, et al. Efficacy of the Intravitreal Sustained-Release Dexamethasone Implant for Diabetic Macular Edema Refractory to Anti-Vascular Endothelial Growth Factor Therapy: Meta-Analysis and Clinical Implications. Ophthalmic Surg Lasers Imaging Retina. 2017;48(2):160–166.
21. Ozurdex. Summary of product characteristics. Available from: https://www.medicines.org.uk/emc/medicine/23422. Accessed on July 25, 2020.

Conclusion 2: Tailoring treatment to patients, non-ocular factors
Systemic disease
• Severe or recent MI, stroke or other thromboembolic events and/ or high
risk for an event, consider corticosteroids of which DEX DDS is recommended first
Compliance to follow up
• In cases where there is a risk of non-compliance, consider corticosteroids of which DEX
DDS is recommended first
• IOP needs to be monitored
MI: Myocardial Infarction; VEGF: Vascular Endothelial Growth Factor.
7. Proposed by authors

Conclusion 3: Tailoring treatment to patients, ocular factors
Presence of glaucoma or high IOP21,22,7
• If uncontrolled, consider anti-VEGFs
• If controlled, consider corticosteroids
Level of ischaemia7
• Some concerns regarding use of anti-VEGFs – not proven, can consider corticosteroids
Lens status7
• In patients with a clear lens, consider anti-VEGFs
• In patients with pseudophakia, consider corticosteroids of which DEX DDS is
recommended first
IOP: Intraocular Pressure; VEGF: Vascular Endothelial Growth Factor.
21 Ozurdex. Summary of product characteristics. Available from: https://www.medicines.org.uk/emc/medicine/23422. Accessed on July 25, 2020.

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