1. DRCRnet
Rationale and Clinical Application of the DRCR.net Anti-VEGF Treatment Algorithm for Proliferative Diabetic Retinopathy
Jennifer K. Sun, MD, MPH
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817  1

2. Purpose Review DRCRnet anti-VEGF treatment algorithm for PDR
Discuss Protocol S data that might provide guidance on managing PDR with anti-VEGF
Frequency of injections given in relation to retinal neovascular status of the treated eye
Time course of neovascularization response

3. Retinal Neovascularization
NV of the iris, NV of the disc, and NV elsewhere*†
Resolved (or Success)
Improved (compared with prior visit)
Stable
Recurrent/Worsened (compared with previous visit, vitreous or preretinal hemorrhage)
Failure: NV growing and worse than baseline after 4 consecutive injections OR NVA
Futility: Persistent NV after 18 months with at least 5 injections over prior 6 months
*Assessment of the angle was required only if NVI was present or the eye met criteria for increased IOP, but was otherwise left to investigator discretion.
†Methods for evaluation of NV status were left to investigators’ discretion based on usual clinical practice

4. Retreatment and Follow-up
Start
With 6 Monthly Injections
Exception: all NV resolved after 4 to 5 injections
Then..
Continue unless NV is resolved or shows “sustained stability” (stable NV compared with last 2 injection visits)
Resume anti-VEGF
IF NV worsens after withholding injections

5. Procedures Used to Assess NV*
Exams: N = 3,410 N %
Extended ophthalmoscopy
2595
76%
Undilated examination of the iris
904
27%
Fundus Photography
471
14%
Fluorescein angiography 80 2%
Ultrasound 3
<1%
*Participants also received slit-lamp and dilated fundus examinations at each visit.

6. Treatment: Number of Injections
Ranibizumab Group Overall
N = 191
Without Vision Impairing DME
N = 147
With Vision Impairing DME
N = 42
Median (IQR) Number of Injections
1st 6 Months
5 (4-6)
2nd 6 Months
2 (1-4)
4 (2-6)
2nd Year
3 (1-6)
3 (1-5)
5 (2-7)
Total
10 (7-14)
10 (6-13)
14 (10-17)
*Note – 2 eyes were missing OCT at baseline and are not included in the DME columns.
Compliance with treatment guidelines for PDR was 97%

7. Neovascularization Status by Visit
At PRIOR visit:
Injections required
2% Worsened
33% Stable
16% Improved
49% Resolved
% of Eyes Receiving Injections at PRIOR Visit R 99 98

8. Neovascularization Status by Visit
Required
unless resolved
At PRIOR visit:
Injections required
8% Worsened
37% Stable
3% Improved
52% Resolved
% of Eyes Receiving Injections at PRIOR Visit R 99 98 56 54

9. Neovascularization Status by Visit
Required
unless resolved
At PRIOR visit:
Injections required
Required unless resolved or sustained stability
2% Failure/Futility
27% Worsened
23% Stable
5% Improved
43% Resolved
% of Eyes Receiving Injections at PRIOR Visit R 99 98 56 54 44 42 39 35 41 40 36 34 29

10. Injections After NV Resolution
Starting at 6 Months: When NV was resolved, investigators chose to inject at 23% of the visits
Median (interquartile range) number of injections between 6 months and 2 years in eyes with resolved NV at 6 months was 4 (1-7) compared with 7 (4-11) for eyes without resolved NV at 6 months (P < .001)

11. Number of Injections After Stability
Stability criteria could only be met after the 6 month visit: N = 153 eyes
At 6 months
37% met stability criteria
22% achieved sustained stability
Investigators chose to administer treatment 15% of the time when sustained stability was met

12. Neovascularization Stability Status by Visit

13. Consecutive Visits With Injection Deferral After Sustained Stability

14. Summary When using the DRCR.net anti-VEGF treatment algorithm for PDR:
The number of injections given is reduced in the second year
Median 7 in the first year vs 3 in the second year
After the first 6 months of treatment, approximately
50% of eyes will achieve NV resolution
>30% will achieve stability
>20% will achieve sustained stability
Most eyes (~90%) in which injections are withheld will need re-injection within 1 year

15. Conclusions
Overall Protocol S results suggest that ranibizumab treatment for PDR following the DRCR.net algorithm is a viable alternative to PRP
Using this algorithm, there is a decreasing treatment burden over the first 2 years of therapy
Longer term Protocol S results are needed to determine whether stabilization of NV can be maintained chronically in eyes with PDR when anti- VEGF therapy is withheld
Eyes in which injections are withheld should be watched closely for possible PDR worsening and need for re-treatment.