Lessons learned from
DRCR.net protocols
Presented by
Sohaib Ali Jawad
3rd year trainee
Iraqi Board of Ophthalmology
Supervised by
Dr. Shatha Anwar
Diabetic retinopathy
It’s a common presenting condition to ophthalmologist especially to retina subspecialist , so its important to
establish a clear , solid , updated clinical approach for an every ophthalmologist
Classification Of DR
Clinical classification of diabetic retinopathy according to Common to use in clinical practice
Background Diabetic Retinopathy Diabetic Maculopathy
Microaneurysm Any retinopathy at the macula
dot blot haemorrhage Oedema and ischemai
exudates
Preproliferative Diabetic Retinopathy Prolifrative Diabetic Retinopathy
Cotton wool spots
Neovascularization of the disc
Venous changes
Neovascularization elsewhere
IRMA
Deep retinal haemorrhage
Advance Diabetic Eye Disease
Tractional Retinal Detachment
Vitreous haemorrhage
Neovascular glaucoma
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ETDRS classification
Clinical classification of diabetic retinopathy according to Early Treatment Diabetic Retinopathy Study
Nonprolifrative diabetic retinopathy
01 02 03
No Retinopathy Very mild NPDR Mild NPDR Any or All:
Normal healthy retina Microaneurysms only Microaneurysms
Review in 12 months. Review in 12 months Retinal haemorrhage
Exudates
Cotton wool spots
No IRMA or beading
Review in 6-12 months
Continued
04 05 06
Moderate NPDR Sever NPDR Very sever NPDR
Sever retinal haemorrhage in 1-3 quadrents 4-2-1 one or more: Tow or more of the criteria for sever NPDR
Or mild IRMA Sever retinal haemorrhage in 4 quadrents Review in 2-3 months
Significant venous beading in no more than 1 Siginficant venous beading in 2 or more
quaderent quadrents
Cotton wool spots Moderate IRMA in 1 or more quadrents
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Proliferative Diabetic Retinopathy
09 08 07
Advance Diabetic Eye High risk PDR Mild-Moderate PDR
Disease NVD about 1/3 disc area NVD or NVE
TRD Any NVD with vitreous haemorrhage Did not meet high risk criteria
VH NVE > ½ disc area with vitreous haemorrhage
NVG Rx according to severity
Treatment should be performed immediately If no Rx , review in 2 months
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High Risk PDR
%85
High Risk PDR criteria :
New vessels on the disc ( NVD ) > 1/3 disc area
Any new vessels of the disc (NVD) with vitreous
haemorrhage
New vessels Elsewhere (NVE) > ½ disc area with
Vitreous haemorrhage.
Clinically significant macular edema
ETDRS
definition of
CSMO
Retinal thickening within 500um of the center of the macula
Exudates within 500um of the center of the macula , if associated with
retinal thickening , it self may be outside the 500um
Retinal thickening one disc area 1500um or > , any part of which within
one disc diameter of the center of the macula.
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Diabetic macular edema
Non central involving Central involving
VA 6/9 or VA 6/9 – 6/90
better
Observation Pseudophakic
Focal / grid Laser Phakic
photocoagulation
Micropulse laser
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Anti – VEGF + Laser
DRCR
Diabetic Retinopathy Clinical Research Network
The DRCR Retina Network supports the The DRCR Retina Netwoek is The DRCR.net was formed in
identification, design, and implementation funded by the National Eye September 2002. In 2018 the Network
of multicenter clinical research initiatives Institute (NEI). The NEI is a part of expanded its scope beyond diabetic
focused on retinal disorders. the National Institutes of Health, retinopathy to consider research on
Principal emphasis is placed on clinical which is the branch of government other retina discorders and the name
trials, but epidemiologic outcomes and that funds medical research. was changed to the DRCR Retina
other research may be supported as well. Networkwww.elite.com
in April of 2019.
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Protocol B
Objectives
Compare IV TA 1 or 4 mg and focal
/ grid macular photocoagulation.
Methods
Age 18 , central involving DME ,
BCVA 20/320 and worse than 20/40
Results
Primary outcome was mean
improvement in vision at 24 months.
Conclusions
TA injections where not superior to
Not Effective
focal / grid photocoagulation and
resulted in more adverse events.
9%-21% > IOP
23%-51% cat Sx
Protocol I
Objectives
Compare combination of Ranibizumab
and focal/grid laser to laser alone , also
Iv TA and focal/grid laser to laser alone
Methods
Age 18 , central involving DME , BCVA
20/32 and worse
Results
Primary outcome was mean
improvement in vision at 12months : >
rani with prompt laser = rani with
deferred laser > TA plus laser
Conclusions
IV Ranibizumab with prompt or deferred laser
24 wks focal/grid had superior VA and OCT
outcome compared to laser alone.
TA plus laser in pseudophakic eyes , although
VA and OCT results non superior to laser alone
but shows similar results to rani group.
Protocol S
Objectives
To evaluate non inferiority of IV ranibizumab
compared with PRP in PDR
Methods
PDR , two groups , one for PRP in 1-3 visits
and another monthly IV ranibizumab
Results
VA improvement much better.
VF loss and vitrectomy frequency , DME
more in PRP group
After 2 years , the eyes had same results in
both groups
Conclusions
In PDR , Rx with ranibizumab resulted in VA
Revolutionary
that was non inferior to ( not worse than )
PRP Rx at 2 years.
HOWEVER
There are important differences in treatment burden, cost and risk of worsening disease if a patient treated with ranibizumab fails
to return for appropriate follow-up.
PRP has a proven track record of long-term stability of PDR regression, with most eyes remaining stable for as long as 15
years after laser with no additional treatment.8 The two-year outcomes thus far don’t allow us confidence in the long-term stability of
PDR treated with ranibizumab alone. The study is planned for five years, so those ongoing results will inform us as we integrate this
data into our clinical practice.
At 5 years, however, the visual field loss in the ranibizumab group approached that in the PRP group. And mean change in VA in the
two groups was similar at 5 years. In the ranibizumab group, fewer patients developed center-involved DME and retinal detachments.
The PRP group had fewer visits and injections. Both groups had an incidence of vitreous hemorrhage of almost 50% throughout the 5
years. Fortunately, substantial vision loss (3 lines or more) was rare in both groups (6%). These results suggest that both PRP and
ranibizumab injection are good options for the treatment of PDR, with similar results at 5 years.
Finally, the most important outcome of this study is the superior vision outcomes with ranibizumab in eyes with PDR and
central DME at baseline
PROTEUS Study
Objectives
Comparison of the efficacy of ranibizumab
intravitreal injections plus (PRP) versus PRP
alone in high risk PDR.
Methods
Eighty-seven participants (aged ≥18 years)
with type 1/2 diabetes and HR-PDR
The RBZ+PRP group received 3 monthly RBZ
injections along with standard PRP. The PRP
monotherapy group received standard PRP
between day 1 and month 2.
Results
At month 12, 92.7% of participants in the
RBZ+PRP group presented NV total reduction
versus 70.5% of the PRP monotherapy
participants. Non DRCR
Conclusions Ongowing
Treatment with RBZ+PRP was more effective study
than PRP monotherapy for NV regression in
HR-PDR participants over 12 months.
Protocol T
Objectives
To compare aflibercept , bevacizumab ,
ranibizumab for the Rx of central involving
DME
Methods
A three-way superiority study
Baseline BCVA ,OCT CMT and volume in
patients with DME , monthly injection regime
Results
Follow up 2 years shows better VA with
aflibrecept > ranibizumab > bevacizumab
Conclusions
Aflibercept , bevacizumab and ranibizumab Response :
improve VA in eyes with central DME , the 5 letters gain VA
relative effect depend on baseline VA. Reduction in OCT
CMT 10%
At worset levels of initial VA , aflibercept and
Reduction in OCT
ranibizumab was more effective at improving
CMV 0.3
vision than bevacizumab do.
HOWEVER
For the overall comparison, aflibercept was superior to the other two agents,. But in year two, the difference between aflibercept
and ranibizumab disappeared, while bevacizumab remained inferior to aflibercept but not ranibizumab
Eyes with worse vision might have thicker maculae due to higher intraocular VEGF levels, and that the agent with the highest VEGF-
binding affinity might be more effective , so aflibercept had the greatest binding affinity.
In the eyes with better baseline vision, bevacizumab reduced edema about 50 % less than the other two agents across the entire two
years of the study. In eyes with worse baseline vision, bevacizumab was less effective than the other two agents in the first year, but in
year two caught up with ranibizumab but not aflibercept.
QUESTIONS NEED ANSWERS
In eyes with better baseline vision, bevacizumab-treated eyes achieved 50 % less reduction in DME on OCT, and were more likely
to require laser. While this didn’t result in worse vision through two years, It concerned that persistent edema in this group might
result in worse vision in the long term unless alternative treatments are given ?
Because it’s more effective at reducing edema and may be more effective at improving vision in eyes with good baseline vision and
thicker maculae than bevacizumab,and also is less expensive than aflibercept, Is it wise to prefer ranibizumab for this subgroup ?
Although in the worse baseline vision subgroup ranibizumab caught up to aflibercept by two years, I believe that the more rapid
improvement seen with aflibercept in the first year cannot be ignored; Can we prefer initiating treatment with that agent in this
subgroup ?
Information on the effectiveness of switching agents when there is persistent edema?
In clinical practice most retinal specialists won’t tolerate persistent swelling and will either switch to a different anti-VEGF agent, add
laser or use steroids when there is persistent edema after three to six injections.
Protocol V
Objectives
center-involved diabetic macular edema and
good vision can confidently be managed by
observation, scheduling anti-VEGF injections
only if vision deteriorates.
Methods
center DME and VA of 20/25 or better were
randomly initial management with Eylea
(aflibercept), laser or observation .
Results
At 2 years, the rates of visual acuity loss of five
or more letters did not differ significantly
between groups
Conclusions
Such a management strategy would avoid
clinical and
potentially unnecessary introduction of anti- economic
VEGF therapies at a stage of disease that may advantages
be amenable to alternative, noninvasive
strategies, such as good systemic control
Protocol U
Objectives
study comparing the addition of a
dexamethasone implant (Ozurdex) to
ranibizumab (Lucentis) in patients who have
continued diabetic macular edema
Methods
OCT CMT 300um and VA of 20/25 patients
who are divided 2 groups , ozurdex + lucentis
and lucentis alone.
Results
no VA benefit in the combination group over
the Lucentis-alone group while there was
significant improvement in CMT in the
combination group. Pseudophakic
Conclusions 5 letters gain
there are definite anatomic benefits to using VS phakic 2
Ozurdex over using Lucentis
letters
ONGOING AND ENROLLING TRIALS
Protocol W
Protocol W is evaluating intravitreous anti-VEGF for the prevention of vision-threatening outcomes (DME or PDR) in patients who present with
severe nonproliferative DR.
Protocol AA
Protocol AA is comparing ultra-widefield fundus imaging to ETDRS seven-standard-fields imaging for the assessment of DR and prediction
rates for worsening of DR.
Protocol AB
Protocol AB is a surgical study evaluating prompt vitrectomy versus anti-VEGF therapy for vitreous hemorrhage
due to PDR.
Protocols TX and AC
Protocol TX is a single-visit 5-year follow-up study of patients who were enrolled in Protocol T. This study will
provide information on long-term VA, changes in treatment, and remission or recurrence of DME after protocol-
specified treatment was stopped.
Protocol AC is an evolution of Protocol T that is examining the real-world cost burden for patients and insurance
systems and considering the potential results of a step-therapy approach to anti-VEGF therapy.
Protocol AE
Protocol AE will investigate the role of daily photobiomodulation therapy for patients with center-involved DME. This would potentially be the
first at-home therapy to treat DR and DME.
HR - PDR
Diabetic macular edema Phakic
p.phakic
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Lessons learned form DRCR.net
Treatment should be initiated with anti-vascular Continuing anti-VEGF monotherapy can result in
endothelial growth factor (VEGF) therapy, and focal/grid continued improvement, even in eyes with persistent DME
laser should be deferred for 6 months. after at least 6 months of therapy. Adding triamcinolone does
not result in better vision outcomes in the short term, and
Protocol I
increases the risk for glaucoma.
Protocol U
In eyes with proliferative DR and co-existing DME, Aflibercept, bevacizumab, and ranibizumab can be
ranibizumab treatment alone should be considered over given in eyes with baseline acuity of 20/32 to 20/40,
combined panretinal photocoagulation (PRP) and bevacizumab reduces edema less effectively and is more
ranibizumab. likely to result in persistent DME.
Protocol S
Protocol T
Visual acuity response at 12 weeks following 3 There is “little evidence” to suggest that switching
monthly injections was associated with the 2-year outcomes, from the DRCR.net’s anti-VEGF treatment regimen for DME
regardless of which anti-VEGF therapy is used. will result in better vision results..
Protocol T
Protocol T
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Lessons learned form DRCR.net
Ranibizumab therapy for DME “may be associated Evaluating DR regression with ranibizumab ,found
with a simultaneous favorable change in diabetic retinopathy ranibizumab significantly improved DR in patients with
severity (DRS) throughout a 5-year period”. moderate to severe nonproliferative DR (NPDR).
Protocol T Protocol T
Optimal number of anti-VEGF injections to achieve Physicians should consider treating earlier stages
or sustain the DR improvement or to evaluate the effect that of DR to prevent the development of vision-threatening
alterations in DRS may have on vision outcomes. Can’t be proliferative DR.
identified”.
Protocol T Protocol V
“When patients were stratified by baseline DR The 5-year outcomes of Protocol S ,although loss to
severity, the highest rates of D improvement were observed follow-up was relatively high, visual acuity in most study eyes
in the moderately severe/severe NPDR group. that completed follow-up was very good at 5 years, which was
consistent with 2-year results..
Protocol T Protocol S
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Lessons learned form DRCR.net
Severe vision loss or serious proliferative DR Patient-specific factors, including anticipated visit
complications were uncommon in either group. The compliance, cost, and frequency of visits, should be
ranibizumab group had lower rates of developing vision- considered when choosing a treatment.”.
impairing DME , Vision-impairing DME developed in 22%
and 38% eyes in the ranibizumab and PRP groups. Protocol S Protocol S
DME can recur after treatments that lead to initial Patients that had been enrolled in Protocols I and
resolution, making follow-up a key component of overall T largely retained their vision gains, but those in Protocol B
treatment did not..
Protocol T Protocol I T B
anti-VEGF therapy for proliferative DR These losses may be “owing to unanticipated health
necessitates ongoing treatment, “in the real world, diabetic issues (33%), financial hardship (17%), noncompliance (33%),
patients are prone to significant losses to follow-up.” and other reasons
Protocol S
Protocol S
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Which DRCR.net protocol has had the
biggest impact on your practice?
If I had to pick only one study that has had the biggest impact on my current practice among the
many important multicenter randomized clinical trials carried out by DRCR.net, it would be ?
Protocol S ? Protocol I ?
PRP, an effective treatment but with drawbacks; It has helped to establish anti-VEGF therapy as the
(permanent VFloss, decreases night vision, exacerbate first-line treatment for center-involved DME; as a result,
DME, takes days-weeks to have an effect, and needs less focal/grid lasers now and use intravitreal steroids
clear media ). as a second-line treatment in most cases.
Protocol S showed some advantages (less diabetic Protocol T ?
macular edema and need for surgery with vitrectomy was
decreased ). helped to fine-tune which of the three anti-VEGF agents
(aflibercept, bevacizumab and ranibizumab) would be
Valuable tool especially in patients with DME, patients beneficial for patients with DME based on baseline
who cannot tolerate full PRP or patients in which the visual acuity and possibly retinal thickness.
view is not sufficient for PRP due to cataract or some
degree of vitreous hemorrhage.
PRP remains a useful tool in long-term management
especially in patients with non-compliance or with
significant traction.
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