1. Diabetic Retinopathy Clinical Research Network
Factors Associated with Worsening Proliferative Diabetic Retinopathy in Eyes Treated with Panretinal Photocoagulation or Ranibizumab (Protocol S)
Susan B. Bressler, M.D. 1

2. Background: PRP vs. Anti-VEGF for PDR as reported in primary paper*
When managing PDR, anti-VEGF injections (ranibizumab) resulted in visual acuity at 2-years that was no worse than (non-inferior† to) PRP (+2.2 letters favoring ranibizumab 95% CI: -0.5, +5.0)
Vision during 2-year course was superior with ranibizumab (area under the curve)
Eyes randomly assigned to ranibizumab were less likely to undergo vitrectomy
Numerically lower rates of vitreous hemorrhage and retinal detachment with ranibizumab compared to PRP (not statistically significant)
*Protocol S Primary Manuscript. JAMA. 2015;314(20)
†5-letter non-inferiority margin

3. Prevalence of Vitrectomy and PDR-Worsening Events at 2 Years as reported in primary paper
Ranibizumab Group
N=191
PRP Group
N=203
P-value
Vitrectomy 4%
15%
< 0.001
Vitreous hemorrhage
27%
34%
0.09
Any retinal detachment 6%
10%
0.08
Neovascular glaucoma 2% 3%
0.50
Neovascularization of the iris 1%
0.96

4. Objectives
Compare the rates and timing of PDR-worsening events individually and as a composite outcome (VH, RD, NVI/NVA, NVG) by treatment group
Explore differences in severity of these events between treatment groups
Identify predictive factors for PDR-worsening events

5. Objective #1: Compare Rates and Timing of PDR-Worsening Events
Composite Outcome: First occurrence of any one of the following:
vitreous hemorrhage,
any retinal detachment,
NVI/NVA or NVG

6. *First occurrence of VH, RD, or NVI/NVG
Composite Outcome*
34%
N = 191
*First occurrence of VH, RD, or NVI/NVG

7. *First occurrence of VH, RD, or NVI/NVG
Composite Outcome*
Ranibizumab vs. PRP
P=0.063
42%
N = 203
34%
N = 191
*First occurrence of VH, RD, or NVI/NVG

8. Composite Outcome*: Eyes Without Baseline CI-DME + Vision Loss
31%
*First occurrence of VH, RD, or NVI/NVG

9. Composite Outcome*: Eyes Without Baseline CI-DME + Vision Loss
Ranibizumab vs. PRP
P=0.008
45%
N = 147
N = 155
31%
*First occurrence of VH, RD, or NVI/NVG

10. Objective #3: Identify Predictive Factors for PDR-Worsening Events

11. 19 Baseline Characteristics Evaluated
Gender
Age
Race/Ethnicity
Diabetes type
Diabetes duration
HbA1c
Hypertension
Best-corrected visual acuity
Central subfield thickness
Vision-Impairing CI-DME
Lens status (phakic vs. pseudophakic)
Vitreous hemorrhage on clinical exam
Neovascularization on clinical exam
NVD or NVE only vs. NVD+NVE
*Diabetic retinopathy severity on fundus photographs (ETDRS)
*Vitreomacular traction
*Epiretinal membrane
^Laser delivery type (single-spot vs. pattern scan)
^Total number of PRP spots (controlling for laser type)
^Number of PRP sittings performed (1 vs. 2 or 3)
Yellow = Subject-level factor
White = Eye-level factor
*Graded by reading center
^PRP group only, subject to inv discretion

12. Evaluating Predictive Factors
Step 1: Evaluated whether each factor had similar effects between groups (testing for an interaction)
Ex) Did the treatment effect comparing the ranibizumab and PRP groups differ according to gender?
There was no strong statistical evidence to suggest that individual factors behaved differently by treatment groups
Therefore, the ranibizumab and PRP groups were combined for evaluation of predictive factors
Analyses controlled for the effect of treatment

13. Evaluating Predictive Factors
Step 2: Each predictive factor was evaluated by itself (univariate analysis)
Step 3: Predictive factors with P < 0.10 were included simultaneously in a model selection process to determine which factors may be the most important (multivariate analysis)

14. Predictive Factors for Composite Outcome* Univariate Analyses
DR Severity Level
NVD+NVE
Vitreous Hemorrhage
Epiretinal Membrane
Age
Race/Ethnicity
PRP Laser Delivery Type†
Gender
Visual Acuity
P < 0.01
0.01 < P < 0.05
0.05 < P < 0.10
*VH, RD, or NVI/NVG
†PRP group only, subject to investigator discretion

15. Predictive Factors for Composite Outcome* Multivariate Analysis
Variable
No. Eyes
Ran
Group
PRP Group
P-value
Hazard Ratio (99% CI)
DR Severity Level†
< 0.001
Moderate PDR (level 65) or better
242
15%
25% -
High risk PDR (71) or worse
146
57%
58%
3.97
(2.48, 6.36)
N’s by group: ≤ lvl 65 = 117 (ran) and 125 (PRP); ≥71 = 72 (ran) and 74 (PRP)
*VH, RD, or NVI/NVG †P-value for ranibizumab-PRP comparison = when adjusting for DRSL (compared with P = unadjusted)

16. Predictive Factors for Composite Outcome* Multivariate Analysis
Variable
No. Eyes
Ran
Group
PRP Group
P-value
Hazard Ratio (99% CI)
DR Severity Level†
< 0.001
Moderate PDR (level 65) or better
242
15%
25% -
High risk PDR (71) or worse
146
57%
58%
3.97
(2.48, 6.36)
PRP Laser Delivery‡
0.008
Single-Spot
164
34%
Pattern scan 39
49%
2.04
(1.02, 4.08)
‡ PRP group only, subject to investigator discretion

17. Summary
In eyes with PDR, rates of PDR-worsening were lower with ranibizumab compared to PRP
Especially among eyes not required to receive ranibizumab at baseline for vision-impairing CI-DME and when adjusting for baseline DR severity
Clinical application of these findings:
While anti-VEGF requires compliance to a more frequent visit schedule than PRP, these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through 2 years of follow-up

18. Summary
The ETDRS Diabetic Retinopathy Severity Scale remains an important predictor for worsening of diabetic retinopathy
Well-known for decades, but still true in this era of anti-VEGF therapy and modern PRP
May support intervention prior to high-risk PDR characteristics
Pattern scan PRP may not be as effective as conventional single-spot PRP in limiting PDR-worsening
Caution: Laser type not assigned randomly, although 68% of investigators that used pattern scan used it exclusively