Transcript Funding Mechanism

Diabetic Retinopathy Clinical
Research Network
Comparative Effectiveness Study of
Aflibercept, Bevacizumab, or
Ranibizumab for DME
Supported through a cooperative agreement from the
National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National
Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817
1
Disclosure
 Funding/Support: Cooperative Agreement with NEI
and NIDDK of NIH, U.S. Department of Health and
Human Services.
 Additional Contributions: Regeneron Pharmaceuticals,
Inc. provided the aflibercept; Genentech Inc. provided
the ranibizumab. Genentech Inc. also provided funding
for blood pressure cuffs and collection of plasma and
urine that are not part of the main study reported
herein.
 A complete list of all DRCR.net investigator financial
disclosures can be found at www.drcr.net.
2
Background
 Diabetic macular edema (DME) affects
~750,000 people in the U.S.
 Intravitreous anti-vascular endothelial
growth factor (anti-VEGF) injections of
either aflibercept (EYLEA), bevacizumab
(Avastin), or ranibizumab (Lucentis) are
effective in treating DME.
 The relative efficacy and safety of these
agents within a head-to-head study were
unknown prior to the results of this trial
3
Background
 Aflibercept and ranibizumab are FDA
approved for DME treatment.
 Bevacizumab is not FDA approved for
intraocular use,
 used “off-label” for DME treatment and
 repackaged into aliquots ~1/500 of
systemic dose in cancer treatments.
 Medicare allowable charges:
 Aflibercept (2.0 mg): $1961
 Bevacizumab (repackaged 1.25mg): $67
 Ranibizumab (0.3 mg): $1189
4
Primary Objective
 For eyes with center involved DME with
decreased visual acuity, compare one year
efficacy and safety of,
1. intravitreous aflibercept (EYLEA®),
2. intravitreous bevacizumab (Avastin®)
and
3. intravitreous ranibizumab (Lucentis®)
Study Design
Randomized, multi-center clinical trial (N = 89 Sites)
Participants meeting all of the following criteria:
• At least 18 years old
• Type 1 or type 2 diabetes
Study eye meeting all of the following criteria:
• ~Snellen equivalent visual acuity 20/32 or worse and 20/320 or
better
• Central-involved DME on clinical exam
• Central subfield (CSF) thickness ≥ protocol-defined gender and
optical coherence tomography (OCT) machine-specific
thresholds
• No history of an anti-VEGF treatment for DME in the past 12
months or any other DME treatment in the past 4 months
Primary Outcome: Change in visual acuity at one year adjusted for
baseline visual acuity using the intent-to-treat principle
6
Pre-Planned Subgroup Analyses
 Preplanned subgroup analyses included only:
•
•
•
•
Baseline visual acuity
Baseline OCT Central Subfield Thickness
Any Prior Anti-VEGF treatment
Lens Status
7
Follow-up Schedule
Baseline to
1 year
• Visits every 4 weeks
• Primary outcome at 1 year
 Visit Procedures
 Refraction with Electronic-ETDRS visual
acuity measurement
 OCT spectral domain (97%) or time domain
 Dilated ocular exam
 Color fundus photos (baseline/1 year only)
ETDRS = Early Treatment Diabetic Retinopathy Study
Treatment Schedule
Through 1 Year (q4 weeks)
 Repeat injections at every 4-week visit if eye
“improved”* or “worsened”*
 Otherwise, defer injections if either:
 Visual acuity 20/20 or better and OCT CST
“normal” or,
 At or after 24 weeks, visual acuity and
OCT stable after 2 consecutive injections
 Resume injections if VA or OCT worsened*
*Improved/worsened defined as:
≥ 5 letter change (~1 Snellen line) from last injection, or,
≥ 10% CST change on OCT from last injection
Treatment Schedule
Through 1 Year
 Focal/grid laser: initiated at or after 24 weeks
only if persistent DME not improving after at
least 2 injections
Randomization
Randomly Assigned Eyes
(one per participant):
N = 660
Baseline
Aflibercept
(2.0 mg)
N = 224
Bevacizumab
(1.25 mg)
N = 218
Ranibizumab
(0.3 mg)
N = 218
One Year
N = 208 (93%)
N = 206 (94%)
N = 206 (94%)
One Year
Excluding
Deaths
94%
97%
96%
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Baseline Characteristics
Aflibercept
(N = 224)
Age (years) – Median
Bevacizumab Ranibizumab
(N = 218)
(N = 218)
61
63
59
49%
47%
43%
White
Black/African
American
65%
64%
67%
14%
17%
17%
Hispanic
17%
17%
14%
Other
4%
3%
3%
Type 2 diabetes
88%
94%
90%
Median HbA1c
7.6
7.7
7.8
Gender: Women
Race
12
Ocular Baseline Characteristics
Aflibercept Bevacizumab Ranibizumab
(N = 224)
(N = 218)
(N = 218)
Mean visual acuity
letter score
(~Snellen Equivalent)
Mean OCT CST (µm)
Any Prior Focal/Grid
Laser
Any Prior Treatment
with anti-VEGF
Phakic
56
(20/80)
57
(20/80)
57
(20/80)
387
376
390
36%
39%
37%
11%
14%
13%
74%
73%
79%
13
Ocular Baseline Characteristics
Aflibercept Bevacizumab Ranibizumab
(N = 224)
(N = 218)
(N = 218)
Diabetic Retinopathy Severity (ETDRS Level)*
Absent or minimal NPDR
(Level 10-20)
Mild to moderately severe
NPDR (Level 35, 43,47)
Severe NPDR (Level 53)
Prior PRP; without current
PDR (Level 60)
Mild to moderate PDR
(Level 31 and 65)
High Risk PDR (Level 71
and 75)
3%
3%
2%
68%
62%
67%
8%
7%
8%
7%
10%
7%
13%
15%
11%
1%
3%
9%
*Missing: aflibercept (3), bevacizumab (7), and ranibizumab (2)
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Treatment for
Diabetic Macular Edema
15
DME Treatment Through 1 Year:
anti-VEGF and Laser
Aflibercept Bevacizumab Ranibizumab
PN = 208
N = 206
N = 206
Value
# of Injections (Max = 13)
Mean
Median
(25th, 75th
percentile)
At least one
focal/grid laser
9.2
9.7
9.4
9 (8, 11)
10 (8, 12)
10 (8, 11)
0.045†
37%
56%
46%
<0.001‡
†Global
(overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons):
aflibercept-bevacizumab: P = 0.045, aflibercept-ranibizumab: P = 0.19, bevacizumab-ranibizumab: P = 0.22.
‡Global
(overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons):
aflibercept-bevacizumab: P<0.001, aflibercept-ranibizumab: P = 0.058, bevacizumab-ranibizumab: P = 0.061.
16
Efficacy
17
Mean Change in Visual Acuity Letter Score
Mean Change in Visual Acuity Letter
Score, Full Cohort
20
18
16
14
12
10
8
6
4
2
0
52 Week Treatment Group Comparison*:
• Aflibercept vs. Bevacizumab P<0.001
• Aflibercept vs. Ranibizumab P = 0.034
• Ranibizumab vs. Bevacizumab P = 0.12
+13
+11
+10
0
4
8 12 16 20 24 28 32 36 40 44 48 52
Weeks
Aflibercept
Bevacizumab
Ranibizumab
* P-values adjusted for baseline visual acuity and multiple comparisons
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Mean Change in Visual Acuity Letter Score
Mean Change in Visual Acuity Letter Score
Baseline Visual Acuity 20/32 to 20/40
20
18
16
14
12
10
8
6
4
2
0
~50% of Cohort
~+8
0
4
8 12 16 20 24 28 32 36 40 44 48 52
Weeks
Aflibercept
Bevacizumab
Ranibizumab
19
Mean Change in Visual Acuity Letter Score
Mean Change in Visual Acuity Letter Score
Baseline Visual Acuity 20/50 or Worse
20
18
16
14
12
10
8
6
4
2
0
~ 50% of Cohort
+19
+14
+12
1-Year Treatment Group Comparison*:
• Aflibercept vs. Bevacizumab P<0.001
• Aflibercept vs. Ranibizumab P = 0.0031
• Ranibizumab vs. Bevacizumab P = 0.21
0
4
8 12 16 20 24 28 32 36 40 44 48 52
Weeks
Aflibercept
Bevacizumab
Ranibizumab
* P-values adjusted for baseline visual acuity and multiple comparisons
20
Subgroup Analysis
Baseline Best-corrected Visual Acuity
Mean Change is Visual Acuity
Letter Score
20/32-20/40
20/50 or worse
20
+19
+14
15
~+8
10
+12
5
0
0
8 16 24 32 40 48
0
Visit Week
Aflibercept
Bevacizumab
8 16 24 32 40 48
Visit Week
Ranibizumab
21
Visual Acuity Mean Change:
Baseline to 1 Year
Mean Change in Visual
Acuity Letter Score
30
25
20
15
10
Aflibercept
Bevacizumab
5
0
Ranibizumab
78-74
(20/32)
73-69
(20/40)
68-64
(20/50)
63-54
(20/63-20/80)
53-24
(20/100-20/320)
Baseline Visual Acuity Letter Score
N=
Aflibercept
54
52
36
29
37
Bevacizumab
41
63
35
38
29
Ranibizumab
46
59
32
37
32
Visual Acuity Outcomes
Baseline = 20/32 to 20/40
Treatment Group
Comparisons
Mean Visual Acuity Letter Score
Observed Data
Difference
8
7.5
8.3
Aflibercept
+0.7
vs
Bevacizumab
CI
-1.3 to
+2.7
PValue
0.69
Aflibercept
-0.4
vs
Ranibizumab
-2.3 to
+1.5
0.69
Ranibizumab
+1.1
vs
Bevacizumab
-0.9 to
+3.1
0.69
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Visual Acuity Outcomes
Baseline = 20/32 to 20/40
>10 Letter Improvement
Treatment Group
Comparisons
Observed Data
Percent
Difference
50%
45%
50%
Aflibercept
+6%
vs
Bevacizumab
Aflibercept
vs
Ranibizumab
CI
-9% to
+21%
PValue
0.82
0%
-13% to
+14%
0.95
Ranibizumab
+6%
vs
Bevacizumab
-10% to
+21%
0.82
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Visual Acuity Outcomes
Baseline = 20/32 to 20/40
>15 Letter Improvement
Treatment Group
Comparisons
Observed Data
Percent
Difference
Aflibercept
+2%
vs
Bevacizumab
18%
16%
15%
Aflibercept
vs
Ranibizumab
+4%
Ranibizumab
-2%
vs
Bevacizumab
CI
-7% to
+11%
PValue
0.73
-5% to
+12%
0.73
-10% to
+7%
0.73
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Visual Acuity Outcomes
Baseline = 20/32 to 20/40
>10 Letter Worsening
Treatment Group
Comparisons
Observed Data
Percent
Difference
Aflibercept
+2%
vs
Bevacizumab
4%
2%
1%
Aflibercept
vs
Ranibizumab
+3%
Ranibizumab
-1%
vs
Bevacizumab
CI
-3% to
+6%
PValue
0.54
-1% to
+7%
0.54
-4% to
+2%
0.54
26
Visual Acuity Outcomes
Baseline = 20/50 or Worse
Treatment Group
Comparisons
Mean Visual Acuity Letter Score
Observed Data
18.9
Difference
14.2
11.8
Aflibercept
+6.5
vs
Bevacizumab
CI
PValue
+2.9 to
+10.1 <0.001
Aflibercept
+4.7
vs
Ranibizumab
+1.4 to
0.0031
+8.0
Ranibizumab
+1.8
vs
Bevacizumab
-1.1 to
+4.8
0.21
27
Visual Acuity Outcomes
Baseline = 20/50 or Worse
>10 Letter Improvement
Treatment Group
Comparisons
Observed Data
Percent
77%
69%
60%
Difference
Aflibercept
+17%
vs
Bevacizumab
CI
PValue
+2% to
+31%
0.018
Aflibercept
+10%
vs
Ranibizumab
-4% to
+23%
0.20
Ranibizumab
+7%
vs
Bevacizumab
-6% to
+20%
0.28
28
Visual Acuity Outcomes
Baseline = 20/50 or Worse
>15 Letter Improvement
Treatment Group
Comparisons
Percent
Observed Data
Difference
67%
50%
41%
Aflibercept
+24%
vs
Bevacizumab
CI
PValue
+9% to
+39% <0.001
Aflibercept
+18%
vs
Ranibizumab
+4% to
0.0078
+32%
Ranibizumab
+6%
vs
Bevacizumab
-7% to
+19%
0.34
29
Visual Acuity Outcomes
Baseline = 20/50 or Worse
>10 Letter Worsening
Treatment Group
Comparisons
Observed Data
Difference
Percent
Aflibercept
-3%
vs
Bevacizumab
1%
4%
2%
CI
-7% to
+2%
PValue
0.56
Aflibercept
-1%
vs
Ranibizumab
-5% to
+3%
0.56
Ranibizumab
-1%
vs
Bevacizumab
-6% to
+3%
0.56
30
Mean Improvement in OCT CSF Thickness from
Baseline (µm)
Overall Mean (µm) Change in OCT
CST Over Time
0
1-Year Treatment Group Comparison*:
• Aflibercept vs. Bevacizumab P < 0.001
• Aflibercept vs. Ranibizumab P = 0.036
• Ranibizumab vs. Bevacizumab P = <0.001
-101
-50
-100
-147
-150
-169
-200
-250
Thinner is decreased DME
0
4
8
12 16 20 24 28 32 36 40 44 48 52
Visit Week
Aflibercept
Bevacizumab
Ranibizumab
31
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
Mean (µm) Change in OCT CST
Baseline visual acuity 20/32 to 20/40
Mean Improvement in OCT CSF
Thickness from Baseline (µm)
0
-50
-67
-100
-119
-129
-150
1-Year Treatment Group Comparison*:
• Aflibercept vs. Bevacizumab P <0.001
• Aflibercept vs. Ranibizumab P = 0.057
• Ranibizumab vs. Bevacizumab P = <0.001
-200
Thinner is decreased DME
-250
0
4
8
12 16 20 24 28 32 36 40 44 48 52
Visit Week
Aflibercept
Bevacizumab
Ranibizumab
32
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
Mean (µm) Change in OCT CST
Mean Improvement in OCT CSF Thickness from
Baseline (µm)
Baseline visual acuity 20/50 or Worse
0
1-Year Treatment Group Comparison*:
• Aflibercept vs. Bevacizumab P < 0.001
• Aflibercept vs. Ranibizumab P = 0.22
• Ranibizumab vs. Bevacizumab P = <0.001
-50
-100
-135
-150
-176
-200
-210
Thinner is decreased DME
-250
0
4
8
12 16 20 24 28 32 36 40 44 48 52
Visit Week
Aflibercept
Bevacizumab
Ranibizumab
33
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
OCT CSF Outcomes
Baseline = 20/32-20/40
Mean OCT CSF Change
Observed Data
Difference
-67
-129
Treatment Group
Comparisons
-119
Aflibercept
-55.8
vs
Bevacizumab
CI
-78.3 to
-32.9
P- Value
<0.001
Aflibercept
-18.2
vs
Ranibizumab
-36.9 to
+0.6
0.057
Ranibizumab
-37.7
vs
Bevacizumab
-59.3 to
-16.1
<0.001
34
Visual Acuity Outcomes
Baseline = 20/32-20/40
CSF <250 µm
Treatment Group
Comparisons
Observed Data
Percent
62%
60%
34%
Difference
Aflibercept
vs
Bevacizumab
CI
PValue
+16% to
+31%
+45%
<0.001
Aflibercept
vs
Ranibizumab
-2%
-16% to
+12%
0.79
Ranibizumab
vs
Bevacizumab
+33%
+17% to
+48%
0.001
35
OCT CSF Outcomes
Baseline = 20/50 or Worse
Mean OCT CSF Change
Observed Data
Treatment Group
Comparisons
Difference
-135
-176
-210
CI
PValue
-121.9 to 49.7
<0.001
Aflibercept
vs
Bevacizumab
-85.8
Aflibercept
vs
Ranibizumab
-18.5
-48.2 to
+11.2
0.22
Ranibizumab
vs
Bevacizumab
-67.3
-101.4 to
-33.1
<0.001
36
Visual Acuity Outcomes
Baseline = 20/50 or Worse
CSF <250 µm
Treatment Group
Comparisons
Percent
Observed Data
70.0
0
Difference
56
39
CI
PValue
Aflibercept
vs
+32%
Bevacizumab
+16%
to
+48%
Aflibercept
+16%
vs
Ranibizumab
+3% to
+30%
0.025
Ranibizumab
+16%
vs
Bevacizumab
+2% to
+29%
0.025
<0.001
37
Safety
38
Ocular Adverse Events
through 1 Year (Study Eye)
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
(N = 218)
No. of injections
prior to 1 year
1991
2055
2011
Endophthalmitis
0
0
0
<1%
<1%
<1%
1.0
0
<1%
<1%
0.55
2%
4%
3%
0.35
<1%
<1%
0
0.55
14%
9%
11%
0.18
Inflammation†
Retinal
detachment/tear
Vitreous
hemorrhage
Injection related
cataract
IOP elevation‡
PValue
†Includes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreous cells.
‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure ≥30 mmHg at
any visit, or initiation of intraocular pressure-lowering medications not in use at baseline. There were no
39
glaucoma surgeries.
IOP= Intraocular Pressure
Ocular Adverse Events
through 1 Year
(Non-Study Eye: Study Drug)
Aflibercept
(N = 129)
No. of injections prior to 1
year
Endophthalmitis
Inflammationǁ
Retinal detachment/tear
Vitreous hemorrhage
Injection related cataract
Intraocular pressure
elevation‡
Bevacizumab Ranibizumab
(N = 122)
(N = 121)
753
841
766
<1%
2%
0
<1%
<1%
0
0
4%
<1%
0
7%
0
0
2%
0
12%
9%
9%
ǁIncludes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreal cells.
‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure
≥30 mmHg at any visit, or initiation of intraocular pressure-lowering medications not in use at
baseline. There were no glaucoma surgeries.
40
Systemic Adverse Events
APTC* through 1-Year
Aflibercept
(N = 224)
Non-fatal MI
Non-fatal stroke
Vascular death
Any APTC Event
Global P = 0.56
Bevacizumab Ranibizumab
(N = 218)
(N = 218)
2%
<1%
1%
0
2%
2%
<1%
2%
1%
3%
4%
5%
* Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention
of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in
various categories of patients. Antiplatelet Trialists' Collaboration. BMJ
1994;308:81-106.
41
Systemic Adverse Events Through 1
Year
Pre-specified (Per Participant)
Aflibercept Bevacizumab
(N = 224)
(N = 218)
Ranibizumab
P(N = 218)
Value*
Death (any cause)
1%
2%
2%
0.72
Hospitalization
21%
18%
22%
0.51
SAEs
26%
21%
25%
0.40
Gastrointestinal †
20%
18%
17%
0.84
Kidney Events‡
13%
11%
11%
0.81
Hypertension
Events
12%
7%
12%
0.20
*Global (overall 3 group comparison) P-value from Fisher’s Exact Test.
†Includes events with a Medical Dictionary for Regulatory Activities system organ class of gastrointestinal disorders
‡Includes a subset of Medical Dictionary for Regulatory Activities system organ class of renal and urinary disorders
events indicative of intrinsic kidney disease, plus increased/abnormal blood creatinine or renal transplant from other 42
system organ classes
SAEs = Serious adverse events
Post Hoc Analysis:
Cardiovascular Events Through 1 Year
Aflibercept
(N = 224)
Any Cardiovascular
Event,† excluding
Hypertension
Any Cardiovascular
Event†
9%
19%
Bevacizumab
(N = 218)
9%
16%
Ranibizumab
(N = 218)
Global P-Value
unadjusted/
adjusted*
17%
0.0121
0.0242
26%
0.0383
0.0814
* Adjusted for potential confounders: gender, age at baseline, Hemoglobin A1c at baseline, diabetes
type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior myocardial
infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status
† Events with a MedDRA system organ class of cardiac disorder or vascular disorder
OR considered
by the medical monitor as related to a cardiac or vascular event (cardiac murmur, cardiac pacemaker
insertion/replacement, coronary arterial stent insertion, heart rate irregular, and stent placement)
Pairwise comparisons (adjusted for multiple comparisons):
1. A-B: P=1.0, A-R: P=0.015, B-R: P = 0.014
2. A-B: P=0.68, A-R: P=0.040, B-R: P = 0.024
3. A-B: P=0.53, A-R: P=0.087, B-R: P = 0.038
4. A-B: P=0.37, A-R: P=0.19, B-R: P = 0.081
43
Post Hoc Analysis:
Cardiovascular Events
Aflibercept
(N = 224)
Bevacizumab Ranibizumab
(N = 218)
(N = 218)
Any Cardiovascular Event
6%
6%
11%
0
2%
5%
Peripheral Vascular
Disease Events
<1%
<1%
<1%
Venous Disease Events
<1%
<1%
<1%
Hypertension Events
12%
7%
12%
Other Cardiovascular
Events
3%
<1%
2%
Cardiac Events
Cerebrovascular Events
44
Discussion
 All three anti-VEGF agents, on average, produced
substantial visual acuity improvement by 1 month,
sustained through 1 year.
 On average, greater improvement occurred with
aflibercept, but relative effect varied by initial visual
acuity.
 Mild initial vision loss (20/32-20/40, 50% of study eyes):
little difference in mean visual acuity at 1 year
 Worse initial vision loss: aflibercept had an advantage
over the other agents
• Statistically significant: Mean improvement of 18.9 for aflibercept vs.
11.8 for bevacizumab (P<0.001) and vs. 14.2 with ranibizumab (P = 0.003)
• Clinically meaningful: For example, relative improvement ≥15 letters (>3
Snellen lines) in 63% more aflibercept-treated eyes than bevacizumabtreated eyes, and 34% more than ranibizumab-treated eyes
45
Discussion
 Bevacizumab had a lesser effect on reducing
macular edema than the other two agents,
regardless of starting acuity.
 Few eyes in any group had substantial visual
acuity loss.
 Median number of injections: 9 to 10 in all three
groups.
 Fewer eyes in the aflibercept group received
focal/grid laser for DME after 24 weeks,
presumably because a greater % of eyes in the
aflibercept group had resolution of central DME
(which drives decision to apply laser).
46
Discussion
 Serious adverse event, death, and
hospitalization rates appeared similar among
treatment groups.
 Significant differences in frequencies of major
cardiovascular events were not identified
• However, post-hoc analysis combining MedDRA
system organ classes of cardiac and vascular resulted
in more participants in the ranibizumab group
reporting these adverse events.
• This is inconsistent with prior studies and may be due
to chance.
 Endophthalmitis was rare: 0.02% of injections.
 No differences in intraocular inflammation.
47
Discussion
 Bevacizumab:
 Note: a central pharmacy repackaged into single use
vials
• Testing was completed for sterility, purity, and
potency, a standard that may not be available in a
clinical practice setting
Results may not apply to eyes with persistent or
recurrent DME already receiving anti-VEGF
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Conclusion
 All three anti-VEGF agents are effective
treatments for DME causing vision
impairment.
 When initial visual acuity loss is mild, on
average there is little difference in visual
acuity at 1-year.
 At worse levels of initial visual acuity
aflibercept is more effective at improving
vision.
49
Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
A complete list of all DRCR.net investigator financial
disclosures and these slides can be found at www.drcr.net.
Full protocol available on clinicalTrials.gov (NCT01627249)
Reference: DOI: 10.1056/NEJMoa1414264
Diabetic Retinopathy Clinical Research Network.
Aflibercept, ranibizumab, or bevacizumab for diabetic
macular edema. NEJM 2015;372:xxx-xxx.
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