1. The Diabetic Retinopathy Clinical Research Network
Exploratory Analysis of Diabetic Retinopathy Progression through 3 Years in a Randomized Clinical Trial Comparing Intravitreal Triamcinolone with Focal/Grid Photocoagulation
Sponsored by the National Eye Institute,
National Institutes of Health, U.S. Department of Health and Human Services

2. Background
Current treatments for reducing the risk of progression of retinopathy:
Glycemic control
PRP – associated with side effects and potential complications
Identification of other treatments is desirable
Rationale for corticosteroids:
Down regulates VEGF and reduces breakdown of blood-retinal barrier
Anti-angiogenic properties
Intravitreal triamcinolone shown to prevent retinal neovascularization in animal and clinical studies

3. DRCR.net Protocol B: Laser vs. Intravitreal Triamcinolone for DME
840 eyes (693 subjects) at 88 sites
Laser group: N = 330
1 mg IVT group: N = 256
4 mg IVT group: N = 254
Major Eligibility Criteria:
VA 20/40 to 20/320
CSF >= 250 microns on OCT
Visits (and retreatment assessment) every 4 months through 3 years
Primary Outcome: VA at 2 years

4. Primary Results
Focal/Grid Laser was more effective (VA and CSF) with fewer side effects (IOP and cataract) than 1 mg or 4 mg IVT at 2 years
Longer term 3 year results were consistent with 2 year results
Change in retinopathy level was a planned secondary outcome
An exploratory analysis was pursued to evaluate effect of IVT on a multilevel definition of progression of retinopathy

5. Outcome Definition
Progression of retinopathy up to 3 years (any of the following):
Progressed from NPDR at baseline to PDR during follow-up*
Received PRP between baseline and follow-up
Reported a vitreous hemorrhage between baseline and follow-up
Worsened 2 or more levels on the ETDRS diabetic retinopathy scale*
*Based on Reading Center grading of annual fundus photos

6. Cumulative Probability* of Progression of Retinopathy
Months
*calculated using the life-table method
Note: 14% were censored prior to 2 yr visit and an additional 34% between the 2 and 3 yr visits (of which only 7% had the potential to complete the 3 yr visit due to early closeout of the study) 6 6

7. Treatment Group Comparisons at 1, 2, and 3 Years
P value*
Laser v 1 mg
0.71
1 Year
Laser v 4 mg
0.03
1 mg v 4 mg
0.08
0.64
2 Years
0.005
0.73
3 Years
0.02
0.07
*From a proportional hazards model adjusting for baseline VA, history of prior macular photocoagulation, and baseline retinopathy severity

8. Cumulative Probability* of Progression of Retinopathy up to 2 Years
Additional Probability
(not counted in prior row)
Laser
N=330
1mg
N=256
4mg
N=254
NPDR to PDR
15%
11% 8%
PRP 9% 6% 5%
Vitreous hemorrhage
Worsened 2 levels 1% 3%
Combined definition
31%
29%
21%
*calculated using the life-table method 8 8

9. Cumulative Probability* of Progression of Retinopathy up to 2 Years
Total Probability
for Each Criteria
Laser
N=330
1mg
N=256
4mg
N=254
NPDR to PDR
15%
11% 8%
PRP
14%
10% 9%
Vitreous hemorrhage
16%
Worsened 2 levels
Combined definition
31%
29%
21%
*calculated using the life-table method 9 9

10. Cumulative Probability* of Progression of Retinopathy up to 3 Years
Additional Probability
(not counted in prior row)
Laser
N=330
1mg
N=256
4mg
N=254
NPDR to PDR
19%
14%
16%
PRP
10% 7% 6%
Vitreous hemorrhage
12% 5%
Worsened 2 levels 2% 3%
Combined definition
37%
35%
30%
*calculated using the life-table method 10 10

11. Cumulative Probability* of Progression of Retinopathy up to 3 Years
Total Probability
for Each Criteria
Laser
N=330
1mg
N=256
4mg
N=254
NPDR to PDR
19%
14%
16%
PRP
18%
11%
12%
Vitreous hemorrhage
20%
15%
Worsened 2 levels
17%
Combined definition
37%
35%
30%
*calculated using the life-table method 11 11

12. Discussion
4 mg IVT can reduce the risk of progression of retinopathy at 1, 2, and 3 years
Difference cannot be explained by an increase in retinopathy caused by focal/grid laser
Similar risk in laser group and 1 mg group
Similar risk of development of PDR in ETDRS immediate laser group (11.1%) and deferred laser group (10.8%)
Results in Fluocinolone Acetonide Implant Study Group trial support DRCRnet results
Lower rate of retinopathy worsening compared to standard of care group (P<0.002, P=0.012, and P<0.015 at 1, 2, and 3 years, respectively)

13. Conclusions
Use of IVT to reduce risk of progression of retinopathy is not warranted at this time
IVT is associated with cataract and elevated IOP
PDR can be treated relatively safely with PRP
Further investigation of treatments to reduce risk of progression of retinopathy safely is needed