Comparing Treatment Efficacy in Diabetic Retinopathy Clinical Trial
"Explore the impact of Intravitreous Aflibercept vs. Vitrectomy with Panretinal Photocoagulation on visual acuity in patients with vitreous hemorrhage from proliferative diabetic retinopathy. Learn about treatment options and study objectives in managing diabetic retinopathy complications effectively."
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DRCR Retina Network Effect of Intravitreous Aflibercept Versus Vitrectomy with Panretinal Photocoagulation on Visual Acuity in Patients with Vitreous Hemorrhage From Proliferative Diabetic Retinopathy: A Randomized Clinical Trial (Protocol AB)
Diabetic Retinopathy Diabetic retinopathy (DR) affects blood vessels in the light-sensitive tissue called the retina that lines the back of the eye. DR is the most common cause of vision loss among people with diabetes and the leading cause of vision impairment and blindness among working-age adults Proliferative diabetic retinopathy (PDR) is the most advanced stage, in which new abnormal blood vessels proliferate on the surface of the retina Without treatment, ~50% of eyes with high-risk PDR experience severe vision loss within 5 years A major complication of PDR that affects vision is vitreous hemorrhage 2 https://nei.nih.gov/health/diabetic/retinopathy
Vitreous Hemorrhage (VH) VH occurs when the abnormal blood vessels in the retina bleed into the vitreous (the gel-like substance that fills the eye) It can look like dark floating spots or streaks across your vision like cobwebs With the advent of new treatments for DR, there are no recent guidelines regarding how to best treat vitreous hemorrhage 3 https://nei.nih.gov/health/diabetic/retinopathy
Treatment Options Vitrectomy Surgery originated in the 1970s An instrument is placed in the eye through a small incision to remove the blood with the vitreous Panretinal photocoagulation (PRP) is often placed intraoperatively Surgical complications and cataract progression still occur Anti-VEGF Injections Shown to be effective for PDR without VH (DRCR Protocol S) Treats the new vessels from PDR while VH can be reabsorbed Previously shown to affect VH in small studies (DRCR Protocol N) Can be performed in-office but requires multiple follow-up injections
Study Objectives 1. Compare efficacy and safety outcomes when initiating treatment with: A. Intravitreous aflibercept injections B. Vitrectomy + panretinal photocoagulation (PRP) 2. Characterize the follow-up course including: Time frame of visual recovery in both groups Percentage initiating aflibercept in the vitrectomy group Percentage undergoing vitrectomy in the aflibercept group 5
Study Design Randomized Multicenter Clinical Trial (N = 39 Sites) Outcomes 205 adults with type 1 or 2 diabetes One study eye with vitreous hemorrhage from PDR 1. Causing vision impairment (20/32 or worse) 2. Requiring intervention Primary Average VA Over 24 Weeks (Area Under the Curve) 2 mg Aflibercept (Vitrectomy prn*) Secondary Treatment With Vitrectomy or Aflibercept During Follow-up Vitrectomy and PRP (Aflibercept prn*) *Based on pre-specified study guidelines 6
Study Visits Surgery within 2 weeks of randomization Recurrent VH treated with 2 monthly aflibercept injections and additionally q 4 weeks as needed Vitrectomy and PRP (Aflibercept prn) All participants had visits at 4, 12, 24, 36, 52, 68, 84, and 104 weeks Injections at baseline, 4, 8, and 12 weeks Starting at 16 weeks, injections could be deferred if successful, Vx performed if persistent VH 2-mg Aflibercept (Vitrectomy prn) NOTE: In both groups, eyes with visual acuity loss from DME were treated with aflibercept based on DRCR Protocol T algorithm 7
Visit Completion (Excluding Deaths) 24 Weeks* Baseline 2-Years** Initial Aflibercept N = 97 (97%) N = 90 (96%) N = 100 Initial Vitrectomy and PRP N = 98 (93%) N = 87 (85%) N = 105 * Overall 24-week completion = 95% ** Overall 2-year completion = 90% 8
Baseline Characteristics Initial Vitrectomy and PRP N = 105 Initial Aflibercept N = 100 Characteristic 56 Age (y), Mean 57 Female / Male 47% / 53% 41% / 59% Type 1 / Type 2 Diabetes 17% / 83% 18% / 82% 8.7 HbA1c (%), Mean 8.3 Hispanic or Latino 43% 39% Race/Ethnicity White 36% 45% Black/African American 16% 10% 5% Other 6% Visual Acuity Letter Score, Mean 36 34 Approximate Snellen Equivalent 20/200 20/250 9
Study Treatment During Follow-up Initial Vitrectomy and PRP N = 105 8% 4% 32% Initial Aflibercept N = 100 Outcome Vitrectomy during follow-up PRP during vitrectomy at follow-up Aflibercept injection during follow-up Number of aflibercept injections through 2 years, mean 33% 32% 99% 8.9 2.3 10
Visual Acuity Over 24 Weeks Primary Outcome Letter score Snellen 20/12 100 20/25 80 20/63 60 Aflibercept vs. Vitrectomy + PRP adjusted difference over 24 weeks: -5.0 letters (95% CI, -10.2 to 0.3) P = .06 40 20/160 20/400 20 Vitrectomy + PRP N = 105 N = 100 0 4 N = 87 N = 90 Aflibercept 0 <20/800 104 12 24 36 52 68 84 Weeks 12 Error bars represent 95% confidence Intervals
Primary Outcome: Average VA Over 24 Weeks (Area Under the Curve) Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value* 59.3 (21.9) 20/63 Initial Aflibercept -5.0 .06 (-10.2 to 0.3) Initial Vitrectomy and PRP 63 (21.7) 20/63 *Adjusted for baseline visual acuity letter score 13
Mean Visual Acuity at 4 Weeks Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value* Initial Aflibercept (N=95) 52.6 (29.4) 20/100 -11.2 .003 Initial Vitrectomy and PRP (N=99) (-18.5 to -3.9) 62.3 (26.8) 20/63 *Adjusted for baseline visual acuity letter score 14
Visual Acuity at 4 Weeks 20/32 or Better (Good Vision) 20/200 or Worse (Poor Vision) % of Eyes % of Eyes 49% 27% 25% 18% Aflibercept Vitrectomy + PRP Aflibercept Vitrectomy + PRP N = 95 N = 99 N = 95 N = 99 P Value CI P Value CI Adjusted Difference Adjusted Difference 11% 0 to 23 .05 -28% -42 to -14 <.001 15
Mean Visual Acuity at 12 Weeks Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value* Initial Aflibercept (N=97) 63.7 (25.0) 20/63 -4.9 .14 Initial Vitrectomy and PRP (N=102) (-11.4 to 1.6) 67.3 (24.7) 20/50 *Adjusted for baseline visual acuity letter score 16
Visual Acuity at 12 Weeks 20/32 or Better (Good Vision) 20/200 or Worse (Poor Vision) 57% % of Eyes % of Eyes 46% 16% 12% Aflibercept Vitrectomy + PRP Aflibercept Vitrectomy + PRP N = 97 N = 102 N = 97 N = 102 P Value CI P Value CI Adjusted Difference Adjusted Difference 6% -3 to 14 .21 -14% -28 to 1 .07 17
Mean Visual Acuity at 24 Weeks Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value* Initial Aflibercept (N=97) 69.4 (23.8) 20/40 -0.5 .88 Initial Vitrectomy and PRP (N=98) (-6.7 to 5.7) 69.0 (23.1) 20/40 *Adjusted for baseline visual acuity letter score 18
Visual Acuity at 24 Weeks 20/32 or Better (Good Vision) 20/200 or Worse (Poor Vision) 63% 60% % of Eyes % of Eyes 10% 10% Aflibercept Vitrectomy + PRP Aflibercept Vitrectomy + PRP N = 97 N = 98 N = 97 N = 98 P Value CI P Value CI Adjusted Difference Adjusted Difference 1% -7 to 8 .85 2% -12 to 16 .75 19
15-Letter Gain at 24 Weeks 72% 70% P % of Eyes Relative Risk CI Value Aflibercept vs. Vitrectomy 0 -12 to 12 .99 Aflibercept Vitrectomy + PRP N = 97 N = 98 20
15-Letter Loss at 24 Weeks* P % of Eyes Relative Risk CI Value Aflibercept vs. Vitrectomy -4 -14 to 6 .53 8% 5% Aflibercept Vitrectomy + PRP N = 64 N = 60 *Excludes eyes with baseline VA <15 letters. 21
Mean Visual Acuity at 2 Years Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value* Initial Aflibercept (N=90) 73.7 (16.4) 20/40 2.7 .36 Initial Vitrectomy and PRP (N=87) (-3.1 to 8.4) 71.0 (24.0) 20/40 *Adjusted for baseline visual acuity letter score 22
Visual Acuity at 2 Years 20/32 or Better (Good Vision) 20/200 or Worse (Poor Vision) 68% 62% % of Eyes % of Eyes 11% 3% Aflibercept Vitrectomy + PRP Aflibercept Vitrectomy + PRP N = 90 N = 87 N = 90 N = 87 P Value CI P Value CI Adjusted Difference Adjusted Difference -6% -13 to 1 .08 -3% -17 to 11 .68 23
15-Letter Gain at 2 Years 76% 75% P % of Eyes Relative Risk CI Value Aflibercept vs. Vitrectomy 2 -7 to 12 .63 Aflibercept Vitrectomy + PRP N = 90 N = 87 24
15-Letter Loss at 2 Years* P % of Eyes Relative Risk CI Value Aflibercept vs. Vitrectomy -6 -19 to 4 .24 11% 5% Aflibercept Vitrectomy + PRP N = 60 N = 53 *Excludes eyes with baseline VA <15 letters. 25
Average Visual Acuity Over 2 Years (Area Under the Curve) Mean VA (SD) Snellen Equivalent Adjusted Difference (95% CI)* P Value Initial Aflibercept (N=90) 68.7 (15.0) 20/50 -2.2 .34 Initial Vitrectomy and PRP (N=87) (-6.7 to 2.3) 70.0 (18.8) 20/40 *Adjusted for baseline visual acuity letter score 26
Visual Outcomes by Treatment Group 24 Weeks 2 Years 100% 80% Percent of Eyes 60% 40% 20% 0% Aflibercept N = 97 Vitrectomy Aflibercept N = 90 Vitrectomy N = 87 N = 98 20/200 or Worse 20/100 to 20/160 20/50 to 20/80 20/32 to 20/40 20/25 20/20 Or Better 27
Center-Involved Diabetic Macular Edema Adjusted Difference (95% CI) 24 Weeks P Value Initial Aflibercept N = 87 8% -23% <.001 (-34 to -34) Initial Vitrectomy and PRP N = 90 31% 2 Years Initial Aflibercept N = 88 17% -4% .48 (-16 to 8) Initial Vitrectomy and PRP N = 80 21% 29
Time to Treatment for Center-Involved Diabetic Macular Edema Aflibercept vs Vitrectomy + PRP Hazard ratio = 0.77 95% CI, 0.41 to 1.46 P = .42 22% 18% 30
Safety 31
Ocular Safety Outcomes Initial Vitrectomy and PRP N = 105 Initial Aflibercept N = 100 Endophthalmitis Any retinal detachment Traction retinal detachment (TRD) Rhegmatogenous retinal detachment Ocular inflammation Visually significant cataract* Cataract extraction* 1% 23% 22% 4% 6% 45% 31% 2% 14% 13% 5% 4% 43% 27% *Evaluated in eyes that were phakic at baseline (N = 75 for aflibercept and 81 for vitrectomy) 32
Ocular Safety Outcomes Tractional Retinal Detachments: Aflibercept Group: identified at or before the first visit when VH cleared sufficiently to allow the investigator a clear view of the retina or the first vitrectomy (whichever occurred first) in 13 eyes (13%) and after that time in 9 eyes (9%); Vitrectomy group: first identified during initial vitrectomy in 13 eyes (12%) and after initial vitrectomy in 1 eye (<1%) 33
Systemic Safety Outcomes Initial Vitrectomy and PRP N = 105 2% Initial Aflibercept N = 100 Nonfatal myocardial infarction 1% Nonfatal stroke Death due to vascular cause or unknown cause Any event above 2% 2% 5% 3% 8% 7% 34
Summary In eyes with vitreous hemorrhage from PDR, there was no significant difference in mean VA letter score over 24 weeks following initial treatment of aflibercept versus vitrectomy with PRP. 1 in 3 eyes assigned to aflibercept underwent vitrectomy; 1 in 3 eyes assigned to vitrectomy initiated aflibercept. Vision improved more quickly with vitrectomy, but long-term vision was similar. Considering the range of the confidence interval, a clinically important benefit in favor of initial vitrectomy with photocoagulation over 24 weeks cannot be excluded. 35
DRCR Retina Network Thank You 36
