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

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)2137-2146

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)

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?

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

Change in Vision Over 2 Years

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

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)

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)

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)

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

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

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

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

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

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

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

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

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

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