Visual Outcomes in Diabetic Retinopathy Trial
Explore the four-year visual outcomes in a randomized trial using intravitreous aflibercept for preventing vision-threatening complications of diabetic retinopathy. Anti-VEGF treatment effectiveness, study design, follow-up visits, and treatment protocols are detailed. Learn about the treatment strategies for proliferative diabetic retinopathy and center-involved diabetic macular edema outcomes.
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Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy 1
Anti-VEGF Treatment Anti-VEGF is effective treatment for center- involved DME and PDR. Can anti-VEGF prevent these vision threatening complications in high-risk eyes? If so, is there visual benefit associated with preventing these complications? 2
Protocol W: Study Design Randomized Multicenter Clinical Trial (N = 64 Sites) 18 years old with type 1 or type 2 diabetes Severe NPDR in at least 1 eye* DRSS between 43 and 53 on reading center grading No evidence of NV on FA within the 7 modified ETDRS fields Best-corrected VA letter score 79 (20/25 or better) No hx of DME/DR treatment within 12 months and 4 prior injections No prior PRP Primary Outcomes 2 mg Intravitreous Aflibercept Development of PDR or CI-DME with vision loss Sham Injection Visual acuity *NPDR determined by investigator; eyes with CI-DME were excluded. After 9 months of recruitment the lower cutoff was modified from 47B 3
Follow-Up Visits and Treatment Month 1 Month 2 Month 4 Month 8 Baseline (0) Month 16 Month 20 Month 12 Before 2 Years: Injections given at every visit Month 28 Month 32 Month 24 2 Years: Injections given if worse than mild NPDR (> level 35 on clinical exam) Month 40 Month 44 Month 36 Final Visit (48M) Participants and VA/OCT/Photo technicians masked to treatment 4
Study Design: PDR Outcome Treatment Following Outcome Treatment with aflibercept initiated if high risk PDR developed Re-treatment with aflibercept followed Protocol S algorithm NVD or NVE on fundus photos or FA TRD, VH, or pre-retinal hemorrhage from PDR on fundus photos, FA or clinical exam NVI, NVA, or NVG on clinical exam TX for PDR without meeting above criteria (anti-VEGF, vitrectomy, PRP)
Study Design: CI-DME Outcome Treatment Following Outcome Treatment with aflibercept initiated if CI-DME with VA loss developed Re-treatment with aflibercept followed Protocol T algorithm CI-DME on OCT with 10% increase in CST from baseline and VA loss from DME: 10 letters loss at a single visit or 5 to 9 letters loss at 2 consecutive visits TX for DME without meeting above criteria (anti-VEGF, corticosteroid, focal/grid laser) 6
Randomization 399 Eyes (328 participants; 36% bilateral) Included in the Primary Analyses 4-years N = 137 (75%)* Aflibercept N = 200 N = 200 N = 134 (73%)* Sham N = 199 N = 199 *Excluding deaths: Aflibercept, N = 17; Sham, N = 16. 7
Participant Baseline Characteristics Aflibercept N = 200 57 42% 94% 8.6 46% 15% 31% 5% 2% Sham N = 199 56 43% 88% 8.3 43% 16% 34% 5% 2% Age (y), median Female Type 2 Diabetes HbA1c (%), median White Black/African American Hispanic or Latino Asian Other Race/Ethnicity 8
Ocular Baseline Characteristics Aflibercept N = 200 Sham N = 199 Visual Acuity Median letter score 88 88 Snellen equivalent 84 Letter Score (20/20 or better) Median OCT CST, m (Spectralis equivalent) Prior DME treatment 20/20 20/20 78% 81% 283 283 10% 11% Anti-VEGF 4% 3% Focal/laser 6% 10% 9
Ocular Baseline Characteristics Aflibercept N = 200 Sham N = 199 Diabetic Retinopathy Severity Scale Graded by Reading Center Moderate NPDR: Level 43 17% 18% Moderately Severe NPDR: Level 47A 33% 31% Moderately Severe NPDR: Levels 47B D 27% 28% Severe NPDR: Level 53 24% 24% 10
PDR or CI-DME Development 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.40 (97.5% CI = 0.28, 0.57); P <0.001 Aflibercept Sham 80% Cumulative Percent 57% 60% 40% 34% 20% 0% 0 1 2 3 4 Year N at risk 200 175 147 119 95 199 154 108 75 64 12
PDR Development 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.42 (97.5% CI = 0.29, 0.61); P <0.001 Aflibercept Sham 80% Cumulative Percent 60% 49% 40% 28% 20% 0% 0 1 2 3 4 Year N at risk 200 177 151 126 103 199 158 123 94 80 13
CI-DME Development 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.51 (97.5% CI = 0.27, 0.97); P 0.02 Aflibercept Sham 80% Cumulative Percent 60% 40% 19% 20% 11% 0% 0 1 2 3 4 Year N at risk 200 180 159 139 124 199 175 146 121 108 14
PDR or CI-DME Development by Baseline DR Severity Adjusted Hazard Ratio (97.5% CI) 0.45 (0.15, 1.37) 0.44 (0.21, 0.93) 0.40 (0.21, 0.75) 0.35 (0.19, 0.67) N Aflibercept Sham Moderate NPDR (Level 43) Moderately Severe NPDR (level 47A) Moderately Severe NPDR (level 47B D) Severe NPDR (level 53) 68 26% 38% 126 26% 47% 109 38% 64% 96 46% 78% 15
Change in DR Severity at 4 Years 2 Step Worsening 2 Step Improvement 100% 100% Adjusted Odds Ratio Aflibercept vs Sham = 0.51 (97.5% CI = 0.28, 0.91); P =0.009 Adjusted Odds Ratio Aflibercept vs Sham = 2.97 (97.5% CI = 1.70, 5.19); P <0.001 80% 80% 60% 60% 54% 40% 40% 29% 23% 20% 20% 11% 0% 0% Aflibercept N = 127 Sham N = 123 Aflibercept N = 127 Sham N = 123 16
Visual Acuity Mean Change 10 Adjusted Mean Difference at 4-Years Aflibercept vs. Sham: -0.5 (-2.3, 1.3); P =0.52 Aflibercept Sham Visual Acuity Mean Change, 7.5 5 Letter Score 2.5 0 -2.4 -2.5 -2.7 -5 -7.5 -10 0 1 2 3 4 Year N = 137 N = 134 N = 200 N = 199 18
Treatments for PDR and DME Aflibercept Sham 4 Years N = 137 N = 134 1 PRP tx for PDR 1% 3% 1 aflibercept injection for PDR or DME 20% 40% 1 focal/grid tx for DME 7% 2% aflibercept injections, mean (SD) 8.7 (5.1) among sham eyes with 1 13.0 (3.7) 3.5 (5.5) 20
Safety 21
Ocular Adverse Events P Aflibercept N = 200 Sham N = 199 Value Endophthalmitis 2% 0% 0.10 Any retinal detachment 1% 1% 1.00 IOP increase 10 mmHg 8% 8% 1.00 IOP 30 mmHg 2% 6% 0.07 Overall frequency of endophthalmitis per aflibercept injection: 0.11% (3 of 2794). Aflibercept injections: Aflibercept group, N = 2231; Sham group, N = 563. 22
Systemic Adverse Events Aflibercept N = 129 Sham N = 128 Bilateral N = 71 P Value Any APTC event* 10% 11% 8% 0.53 Nonfatal myocardial infarction Nonfatal stroke 1% 2% 2% 1% 2% 2% Death due to vascular or unknown cause 7% 7% 4% Hypertension 14% 22% 11% *APTC = Antiplatelet Trialists Collaboration 23
Conclusion Among patients with NPDR (DRSS level 43-53) and good vision (20/25 or better) but without CI-DME, early aflibercept compared with initial observation and treatment if disease worsened resulted in A statistically significant reduction in the probability of developing PDR or CI-DME within 4 years No difference in visual acuity at 4 years 24
