1. Diabetic Retinopathy Clinical Research Network
Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Should Baseline Characteristics Affect Choice of Treatment?
(Protocol S)  1

2. Background: PRP vs. Anti-VEGF for PDR*
For eyes with PDR, change in visual acuity at 2 years with anti-VEGF injections (ranibizumab) was non-inferior (5-letter margin) to panretinal photocoagulation (PRP)
+2.2-letter (95% CI: -0.5, +5.0) adjusted difference favoring ranibizumab
Ranibizumab resulted in superior change in visual acuity over 2 years (area under the curve) and reduced development of DME
*Protocol S Primary Manuscript. JAMA. 2015;314(20)

3. Superiority of Ranibizumab vs
Superiority of Ranibizumab vs. PRP Pre-specified 2 year secondary outcomes as reported in primary paper
Ranibizumab Group
PRP Group
P value
Change in VA Over 2 Years (Area Under the Curve)
+4.5 letters
-0.3 letters
< .001
Incident CI-DME + Vision Impairment (20/32 or worse)* 9%
28%
*Among eyes without CI-DME + vision impairment at baseline (~75% of eyes)

4. Objectives
Explore whether baseline characteristics impact the direction or magnitude of the benefit of ranibizumab over PRP
Outcomes:
Change in visual acuity over 2 years
Development of center-involved DME with vision impairment (20/32 or worse) by 2 years
Methods: test for statistical interaction
Does the characteristic modify the treatment group difference?

5. 25 Baseline Characteristics Evaluated
Sex
Age
Race/Ethnicity
Diabetes type
Diabetes duration
HbA1c
Mean arterial pressure
Hypertension
Prior treatment for DME
Prior focal/grid laser for DME
Prior anti-VEGF for DME
Vitreous hemorrhage on clinical exam
Visual acuity
Lens status (phakic vs. pseudophakic)
Neovascularization on clinical exam
NVD or NVE only vs. NVD+NVE
OCT central subfield thickness
OCT retinal volume
*Epiretinal membrane
*Vitreomacular traction
*Cystoid abnormalities
*Subretinal fluid
*Diabetic retinopathy severity on fundus photographs (ETDRS level)
*Hemorrhages or microaneurysms
*Hard exudates
*Surface wrinkling retinopathy
Lime = Subject-level factor
White = Eye-level factor
*Graded by reading center
Italics indicates continuous variable

6. Change in Vision Over 2 Years

7. Change in Vision Over 2 Years Participant Characteristics
Ran N
PRP N
Adjusted Difference* (95% CI)
P value
Mean arterial pressure (mmHg)**
< 100 (e.g.<140/80) 88 93
3.8 (2.0, 5.6)
.03
≥ 100 (e.g.>140/80) 72 75
5.4 (3.4, 7.4)
*All analyses were adjusted for baseline vision and OCT central subfield thickness
**Numeric variables were analyzed as continuous and dichotomized for tabulation only

8. Change in Vision Over 2 Years Ocular Characteristics
Ran N
PRP N
Adjusted Difference (95% CI)
P value
Prior focal/grid laser treatment for DME No
131
143
5.1 (3.7, 6.5)
.03
Yes 29 25
1.0 (-2.3, 4.4)

9. Change in Vision Over 2 Years Ocular Characteristics
Ran N
PRP N
Adjusted Difference (95% CI)
P value
Prior focal/grid laser treatment for DME No
131
143
5.1 (3.7, 6.5)
.03
Yes 29 25
1.0 (-2.3, 4.4)
Neovascularization on clinical exam
NVD or NVE only
103
107
3.6 (1.9, 5.2)
.04
NVD and NVE 51 57
6.7 (4.4, 9.1)

10. Change in Vision Over 2 Years Ocular Characteristics
Ran N
PRP N
Adjusted Difference (95% CI)
P value
Prior focal/grid laser treatment for DME No
131
143
5.1 (3.7, 6.5)
.03
Yes 29 25
1.0 (-2.3, 4.4)
Neovascularization on clinical exam
NVD or NVE only
103
107
3.6 (1.9, 5.2)
.04
NVD and NVE 51 57
6.7 (4.4, 9.1)
DR severity (ETDRS)
Moderate PDR (level 65) or better 99
106
3.8 (2.1, 5.5)
.02
High-risk PDR (level 71) or worse 59
6.1 (3.9, 8.4)

11. Change in Vision Over 2 Years Interaction With DR Severity Level
+3.8 Letters
N=99
N=106
N=59
N=59

12. Change in Vision Over 2 Years Interaction With DR Severity Level
Interaction P = .02
+3.8 Letters
+6.1 Letters
N=99
N=106
N=59
N=59

13. Summary Change in Vision Over 2 Years
No characteristics associated with superiority of PRP over ranibizumab
Greater benefit of ranibizumab among participants with higher mean arterial pressure
Greater benefit of ranibizumab among eyes without prior focal/grid laser for DME, and more advanced neovascularization
Eyes with high-risk PDR had even greater treatment benefit when managed with ranibizumab; this was driven by greater vision loss in the PRP

14. Development of CI-DME with Vision Impairment Eyes without baseline CI-DME and vision impairment
Adjusted hazard ratio*: Ranibizumab vs. PRP 0.26 (0.14 to 0.46, P <.001)
N = 155
N = 147
*<1 indicates benefit of ranibizumab

15. Adjusted Ran/PRP Hazard Ratio (95% CI)*
Development of CI-DME with Vision Impairment Participant Characteristics
Characteristic
Ran N
PRP N
Adjusted Ran/PRP Hazard Ratio (95% CI)*
P value
Race/ethnicity
White 79 70
0.50 (0.24, 1.03)
.01
Non-White 67 82
0.10 (0.03, 0.30)
*<1 indicates benefit of ranibizumab

16. Adjusted Ran/PRP Hazard Ratio (95% CI)*
Development of CI-DME with Vision Impairment Participant Characteristics
Characteristic
Ran N
PRP N
Adjusted Ran/PRP Hazard Ratio (95% CI)*
P value
Race/ethnicity
White 79 70
0.50 (0.24, 1.03)
.01
Non-White 67 82
0.10 (0.03, 0.30)
Mean arterial pressure
< 100 mmHg (e.g.<140/80) 84 83
0.39 (0.17, 0.87)
≥ 100 mmHg (e.g.>140/80) 63 72
0.16 (0.07, 0.41)
*<1 indicates benefit of ranibizumab

17. Summary Development of CI-DME with Vision Impairment
No characteristics associated with superiority of PRP over ranibizumab
Greater benefit of ranibizumab in non-white participants, and in participants with higher mean arterial pressure
No interactions identified among ocular characteristics

18. Summary Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Should Baseline Characteristics Affect Choice of Treatment?
Caution: Due to the large number of statistical comparisons and post hoc design, these results should be viewed as hypothesis-generating and require confirmation in future studies
No baseline characteristics were associated with a reversal of our findings: PRP was never superior to ranibizumab for VA area under the curve and incident vision impairing DME
Several quantitative interactions were identified suggesting some particiapnts will do even better than others when an anti-VEGF approach is selected
Results provide additional support that ranibizumab
may be reasonable alternative to PRP for PDR over 2 years

19. Summary Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Should Baseline Characteristics Affect Choice of Treatment?
Caution: Due to the large number of statistical comparisons and post hoc design, these results should be viewed as hypothesis-generating and require confirmation in future studies
No baseline characteristics were associated with a reversal of our findings: PRP was never superior to ranibizumab for VA area under the curve and incident vision impairing DME
Results provide additional support that ranibizumab
may be reasonable alternative to PRP for PDR over 2 years,
Particularly among those with high blood pressure and
more advanced grades of PDR

20. Thank You on Behalf of the Diabetic Retinopathy Clinical Research Network (DRCR.net)20