1. Diabetic Retinopathy Clinical Research Network
Aflibercept, Bevacizumab, or Ranibizumab for DME: Two-year Results
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

2. 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.

3. Background
DRCR.net trial: Comparative effectiveness of aflibercept, bevacizumab, and ranibizumab for center-involved diabetic macular edema (DME) associated with vision impairment.
At 1-year: all agents, on average, improved VA. Relative treatment effect on VA depended on initial visual acuity or OCT central subfield thickness (CST)
When baseline VA impairment or OCT CST was mild, no differences on average were identified
At worse levels of baseline VA impairment or thicker OCT CST, aflibercept more effective
No statistical differences in pre-specified ocular/systemic safety outcomes

4. Randomized, multi-center clinical trial (89 Sites)
Study Design
Randomized, multi-center clinical trial (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

5. Change in visual acuity at 1 Yr (primary outcome) and 2 Yrs
Main Outcome
Change in visual acuity at 1 Yr (primary outcome) and 2 Yrs
Adjusted for baseline visual acuity and multiple comparisons
Multiple imputation for missing values, intent-to-treat principle
Truncated to 3 SD from the mean
Aflibercept
vs.
Bevacizumab
Aflibercept
vs.
Ranibizumab
Bevacizumab
vs.
Ranibizumab
Visits were every 4 weeks during year-1 and 4 to 16 weeks during year-2, depending on treatment course
Starting at the 6-month visit, focal/grid laser treatment was administered if DME persisted and was not improving
Participants unmasked to treatment group following the publication of the 1yr primary results: though discouraged, decision could be made at that time to switch to a non-study anti-VEGF agent.
Doses: aflibercept 2.0-mg; bevacizumab 1.25-mg; ranibizumab 0.3-mg

6. Ocular Baseline Characteristics
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
Median visual acuity letter score
(~Snellen Equivalent) 69
(20/40) 68
(20/50)
Median OCT CST* (µm)
387
376
390
Any Prior Focal/Grid Laser
36%
39%
37%
Any Prior Treatment with anti-VEGF
11%
14%
13%
Phakic
74%
73%
79%
*Time domain (Stratus®) equivalent

7. Randomly Assigned Eyes (one per participant): N = 660
Randomization
Randomly Assigned Eyes
(one per participant): N = 660
Aflibercept (2.0 mg/0.05mL)
N = 224
Bevacizumab (1.25 mg/0.05mL)
N = 218
Ranibizumab
(0.3 mg/0.05mL)
N = 218
Baseline
1-year
(excluding deaths)
95%
97%
96%
90%
85%
88%
2-Years
2-Years
(excluding deaths)
91%
90%
91%

8. Visits and Treatment for Diabetic Macular Edema

9. # of Visits in Year 2* (Completers Only)
Aflibercept
N = 201
Bevacizumab
N = 185
Ranibizumab
N = 192
Mean
9.4
9.3
Median
(25th, 75th percentile)
10 (8, 12)
10 (7, 12)
10 (7, 12) 
* Protocol required monthly visits in year 1 for all 3 groups

10. DME Treatment: anti-VEGF (Completers of the given visit only)
Aflibercept
Bevacizumab
Ranibizumab‡
Global P-Value
# of Injections: Median (25th, 75th percentile)
Year 1
9 (8, 11)
10 (8, 12)
10 (8, 11) 
0.045†
Year 2
5 (2, 7)
6 (2, 9)
6 (2, 9) 
0.32
Over 2 Years
15 (11, 17)
16 (12, 20)
15 (11, 19) 
0.08
NOTE: 98% of protocol required re-injections were given over 2 years
† Pairwise comparisons (adjusted for multiple comparisons): A-B: P = 0.045, A-R: P = 0.19, B-R: P = 0.22.
‡Seven study eyes received 1 injection and 2 eyes received 2 injections of 0.5-mg of ranibizumab prior to the FDA approving a 0.3 –mg dosage of ranibizumab for DME treatment and protocol revision to use 0.3-mg dose

11. DME Treatment: Laser (Completers of the given visit only)
Aflibercept
Bevacizumab
Ranibizumab
Global P-Value
At least one focal/grid laser
Year 1
37%
56%
46%
<0.001*
Year 2
20%
31%
27%
0.046‡
Over 2 Years
41%
64%
52%
<0.001†
*Pairwise comparisons (adjusted for multiple comparisons): A-B: P<0.001, A-R: P=0.06, B-R: P=0.06
‡ Pairwise comparisons (adjusted for multiple comparisons): A-B: P=0.046, A-R: P=0.12, B-R: P=0.37.
†Pairwise comparisons (adjusted for multiple comparisons): A-B: P<0.001, A-R: P=0.04, B-R: P=0.01.

12. Efficacy

13. Mean Change in Visual Acuity Over 2 Years Full Cohort
+13.3
+12.8
+11.2
+12.3
+10.0
+9.7
104-Week Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P = 0.02
Aflibercept vs. Ranibizumab P = 0.47
Ranibizumab vs. Bevacizumab P = 0.11
* P-values adjusted for baseline visual acuity and multiple comparisons

14. Mean Change in Visual Acuity Over 2 Years Baseline Visual Acuity 20/32 to 20/40
~50% of Cohort
104-Week Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P = 0.51
Aflibercept vs. Ranibizumab P = 0.51
Ranibizumab vs. Bevacizumab P = 0.31
+8.3
+8.6
+8.0
+7.5
+7.8
+6.8
* P-values adjusted for baseline visual acuity and multiple comparisons

15. Mean Change in Visual Acuity Over 2 Years Baseline Visual Acuity 20/50 or Worse
~50% of Cohort
+18.1
+18.9
+16.1
+14.2
+13.3
+11.8
104-Week Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P = 0.02
Aflibercept vs. Ranibizumab P = 0.18
Ranibizumab vs. Bevacizumab P = 0.18
* P-values adjusted for baseline visual acuity and multiple comparisons

16. Mean Change in Visual Acuity Over 2 Years By Baseline Visual Acuity Subgroup

17. Baseline Visual Acuity
Mean Change in Visual Acuity at 2 Years By Baseline Visual Acuity Level
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
N =
Aflibercept 52 51 32 29 37
Bevacizumab 39 54 36 24
Ranibizumab 44 53 33

18. ≥10 Letter Improvement at 2 Years Baseline Visual Acuity 20/32 to 20/40
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept vs Bevacizumab
+9%
-7% to +25%
0.52
Aflibercept vs
Ranibizumab
+4%
-10% to +17%
0.59
Ranibizumab vs Bevacizumab
+5%
-8% to +19%
* P-values adjusted for baseline visual acuity and multiple comparisons

19. ≥15 Letter Improvement at 2 Years Baseline Visual Acuity 20/32 to 20/40
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept vs Bevacizumab
+1%
-10% to +11%
0.89
Aflibercept vs
Ranibizumab
+2%
-8% to +11%
Ranibizumab vs Bevacizumab
-1%
-11% to +10%
* P-values adjusted for baseline visual acuity and multiple comparisons

20. ≥10 Letter Worsening at 2 Years Baseline Visual Acuity 20/32 to 20/40
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept vs Bevacizumab
-6% to +5%
0.96
Aflibercept vs
Ranibizumab
+3%
-3% to +8%
0.55
Ranibizumab vs Bevacizumab
-3%
-8% to +3%
* P-values adjusted for baseline visual acuity and multiple comparisons

21. ≥10 Letter Improvement at 2 Years Baseline Visual Acuity 20/50 or worse
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept vs Bevacizumab
+10%
-6% to +26%
0.35
Aflibercept vs
Ranibizumab
+3%
-9% to +15%
0.57
Ranibizumab vs Bevacizumab
+7%
-6% to +20%
* P-values adjusted for baseline visual acuity and multiple comparisons

22. Treatment Group Comparisons* Ranibizumab vs Bevacizumab
≥15 Letter Improvement at 2 Years Baseline Visual Acuity 20/50 or worse
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept
vs Bevacizumab
+8%
-9% to +25%
0.74 vs
Ranibizumab
+2%
-11% to +15%
0.75
Ranibizumab vs Bevacizumab
+6%
-8% to +20%
* P-values adjusted for baseline visual acuity and multiple comparisons

23. ≥10 Letter Worsening at 2 Years Baseline Visual Acuity 20/50 or worse
Treatment Group Comparisons*
Adjusted Difference CI
P- Value
Aflibercept
vs Bevacizumab
-3%
-10% to +3%
0.49 vs
Ranibizumab
+2%
-3% to +7%
Ranibizumab vs Bevacizumab
-5%
-13% to +3%
0.33
* P-values adjusted for baseline visual acuity and multiple comparisons

24. Mean Change in Visual Acuity at 2 Years Other Pre-Specified Subgroups
Baseline Subgroup
Aflibercept
Bevacizumab
Ranibizumab
P-Value for inter- action
CSF <400
10.9
8.4
11.8
0.68
CSF >400
15.0
11.5
13.0
No Prior Anti-VEGF
10.6
12.7
0.45
Prior Anti-VEGF
11.4
7.6
9.7
Pseudophakic
12.8
8.2
0.69
Phakic
12.9
10.7
12.5

25. Mean Change in OCT CST Over 2 Years Full Cohort
2-Year Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P<0.001
Aflibercept vs. Ranibizumab P = 0.08
Ranibizumab vs. Bevacizumab P = 0.001
-101
-126
-147
-149
-169
-171
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons

26. Mean Change in OCT CST Over 2 Years Baseline Visual Acuity 20/32 to 20/40
-67
-68
-119
-125
-129
-133
2-Year Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P<0.001
Aflibercept vs. Ranibizumab P=0.26
Ranibizumab vs. Bevacizumab P<0.001
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons

27. Mean Change in OCT CST Over 2 Years Baseline Visual Acuity 20/50 or Worse
2-Year Treatment Group Comparison*:
Aflibercept vs. Bevacizumab P = 0.01
Aflibercept vs. Ranibizumab P = 0.19
Ranibizumab vs. Bevacizumab P = 0.19
-135
-174
-176
-185
-210
-211
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons

28. OCT CST <250 µm at 2 Years Baseline Visual Acuity 20/32 to 20/40
Treatment Group Comparisons
Adjusted Difference CI
P- Value
Aflibercept
vs Bevacizumab
+33%
+17% to +49%
<0.001 vs
Ranibizumab
+2%
-12% to +15%
0.81
+32%
+16% to +47%
* P-values adjusted for baseline OCT, visual acuity and multiple comparisons

29. OCT CST <250 µm at 2 Years Baseline Visual Acuity 20/50 or worse
Treatment Group Comparisons
Adjusted Difference CI
P- Value
Aflibercept vs Bevacizumab
+31%
+14% to +47%
<0.001
Aflibercept vs
Ranibizumab
+12%
-1% to +25%
0.08
Ranibizumab vs Bevacizumab
+19%
+2% to +35%
0.02
* P-values adjusted for baseline OCT, visual acuity and multiple comparisons

30. Safety

31. Pre-Specified Ocular Adverse Events through 2 Years (Study Eyes)
% of eyes with at least 1 event
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
Global P-Value
No. of injections
2998
3115
3066
Endophthalmitis*
<1%
0.66
Inflammation† 3% 1% 2%
0.69
Retinal detachment/tear
1.0
Vitreous hemorrhage 7% 8% 5%
0.37
Injection-related cataract
0.38
IOP elevation‡
17%
12%
16%
0.31
†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, or glaucoma surgery.
*Non-study eyes: endophthalmitis in <1% in aflibercept and ranibizumab groups; 0 in bevacizumab group.

32. Pre-Specified Ocular Adverse Events through 2 Years (Non-Study Eyes Receiving Study Drug)
% of eyes with at least 1 event
Aflibercept
(N = 144)
Bevacizumab
(N = 134)
Ranibizumab
(N = 132)
No. of injections
1180
1316
1225
Endophthalmitis
<1%
Inflammation† 2%
Retinal detachment/tear
Vitreous hemorrhage 8% 9% 7%
Injection related cataract 1%
Intraocular pressure elevation‡
13%
11%
14%
†Includes 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, or glaucoma surgery.

33. Pre-specified APTC* Adverse Events through 2 Years
% of pts with at least one event
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
Global P-Value
Non-fatal MI 3% 1%
Non-fatal stroke
<1% 5%
Vascular death 4%
Any APTC Event 8%
12%
0.047†
†Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = 0.34, aflibercept-ranibizumab: P = 0.047, bevacizumab-ranibizumab: P = 0.20.
Global P-value adjusting for 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: P = 0.09.
* Antiplatelet Trialists’ Collaboration. 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:

34. Post Hoc Analysis of APTC Adverse Events Stratified by Prior MI/Stroke
% of pts with at least one event
Aflibercept
Bevacizumab
Ranibizumab
No Prior MI/Stroke
N = 203
N = 193
Non-fatal MI
Non-fatal stroke
Vascular death
Any APTC Event
Prior MI/Stroke
N = 21
N = 25

35. Post Hoc Analysis of APTC Adverse Events Stratified by Prior MI/Stroke
% of pts with at least one event
Aflibercept
Bevacizumab
Ranibizumab
No Prior MI/Stroke
N = 203
N = 193
Non-fatal MI 3% 2%
Non-fatal stroke
<1%
Vascular death 4%
Any APTC Event 5% 6% 9%
Prior MI/Stroke
N = 21
N = 25

36. Post Hoc Analysis of APTC Adverse Events Stratified by Prior MI/Stroke
% of pts with at least one event
Aflibercept
Bevacizumab
Ranibizumab
No Prior MI/Stroke
N = 203
N = 193
Non-fatal MI 3% 2%
Non-fatal stroke
<1%
Vascular death 4%
Any APTC Event 5% 6% 9%
Prior MI/Stroke
N = 21
N = 25 8%
20%
16%
10%
36%
Global P-value adjusting prior myocardial infarction, prior stroke: P = 0.06.

37. Other Pre-Specified Systemic Adverse Events through 2 Years
% of pts with at least one event
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
Global P-Value
Death (any cause) 2% 6% 5%
0.12
Hospitalization
34%
33%
0.93
SAEs*
39%
37%
38%
0.90
Gastrointestinal†
30%
29%
28%
0.85
Kidney Events‡
22%
21%
16%
0.22
Hypertension Events
17%
12%
20%
0.08
†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 system organ classes
*SAEs = Serious adverse events

38. Post Hoc Analysis: Cardiovascular Events* through 2 Years
% of pts with at least one event
Aflibercept
(N = 224)
Bevacizumab
(N = 218)
Ranibizumab
Global P-Value
Any Cardiovascular Event, excluding Hypertension
20%
22%
27%
0.18
Any Cardiovascular Event
31%
32%
38%
0.26
* 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, heart transplant, implantable defibrillator insertion, stent placement, and troponin increased. )

39. Discussion At one year:
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 worse levels of initial visual acuity, aflibercept is more effective at improving vision.

40. Discussion
At 2 years:
Vision gains (from baseline) were seen with all three drugs at 2 years, with reduced number of injections and lasers in year 2
When initial visual acuity loss is mild, on average there is still little difference in visual acuity.
At worse levels of initial visual acuity aflibercept was more effective at improving visual acuity versus bevacizumab, but not ranibizumab.

41. Discussion
Few eyes in any group lost substantial amounts of visual acuity
In worse VA subgroup:
At one year, percentage in the aflibercept group gaining 15 or more letters was 63% and 34% greater (relative difference) than that of the bevacizumab and ranibizumab groups, respectively
At 2 years
The percentage in aflibercept group gaining >15 letters was 12% and 5% greater (relative difference), respectively
The percentage in aflibercept group gaining >10 letters was 15% and 7% greater (relative difference), respectively

42. Discussion
At year one, bevacizumab was found to reduce retinal thickness less than the other 2 agents. This difference persisted in year 2 in the eyes with better initial visual acuity.
In eyes with worse initial visual acuity, the mean change in CST was significantly worse only in the bevacizumab group compared with aflibercept

43. Discussion
In year 2, ~half the number of injections were indicated per protocol as in year 1 in each group.
Cumulative number of injections was similar across all groups
Similar to year 1, laser treatment was indicated per protocol less frequently in the aflibercept-treated eyes in year two.
Since focal/grid laser to persistent DME after the 24-week visit was a protocol-defined part of the treatment regimen, it is not possible to separate the effect of macular laser from the anti-VEGF treatment on the VA and thickness outcomes after the 6-month visit.

44. Discussion
Pre-defined systemic APTC rates were higher in the ranibizumab group
Consisting of more non-fatal strokes and vascular deaths in the ranibizumab group.
Although P-values increased slightly after adjusting for a history of prior stroke or MI and other potential confounders, this did not alter the results substantially.
These findings have not been demonstrated consistently in previously reported clinical trials.

45. 2 Year APTC Event Rates Across DME Studies of Anti-VEGF Agents

46. 2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs. Control
Study
Treatment Group
Control
(Laser or Sham)
Ranibizumab
0.3 mg
0.5 mg N %
RISE/RIDE Pooled
250
5.2%
5.6%
7.2%
RISE
123
4.9%
125
2.4%
126
8.7%
RIDE
127
5.5%
8.8%
124
DRCR.net Protocol I
130
13%
375 7%
RESTORE
110
4.5%
235
3.4%

47. 2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs. Control
RISE and RIDE: Higher percentage in the pooled 0.5-mg ranibizumab group than in the 0.3-mg ranibizumab or control group.
In RISE, 0.3-mg ranibizumab had the lowest rate among the 3 treatment groups and in RIDE it had the highest.
Study
Treatment Group
Control
(Laser or Sham)
Ranibizumab
0.3-mg
0.5-mg N %
RISE/RIDE Pooled
250
5.2%
5.6%
7.2%
RISE
123
4.9%
125
2.4%
126
8.7%
RIDE
127
5.5%
8.8%
124
DRCR.net Protocol I
130
13%
375 7%
RESTORE
110
4.5%
235
3.4% f

48. 2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs. Control
Protocol I: Fewer events in the ranibizumab group than in the laser group
Study
Treatment Group
Control
(Laser or Sham)
Ranibizumab
0.3-mg
0.5-mg N %
RISE/RIDE Pooled
250
5.2%
5.6%
7.2%
RISE
123
4.9%
125
2.4%
126
8.7%
RIDE
127
5.5%
8.8%
124
DRCR.net Protocol I
130
13%
375 7%
RESTORE
110
4.5%
235
3.4%

49. 2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in DME Studies Comparing Ranibizumab vs. Control
RESTORE: Similar rates in the ranibizumab and laser group
Study
Treatment Group
Control
(Laser or Sham)
Ranibizumab
0.3-mg
0.5-mg N %
RISE/RIDE Pooled
250
5.2%
5.6%
7.2%
RISE
123
4.9%
125
2.4%
126
8.7%
RIDE
127
5.5%
8.8%
124
DRCR.net Protocol I
130
13%
375 7%
RESTORE
110
4.5%
235
3.4%

50. 2 Year APTC Event Rates in AMD Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in AMD Studies Comparing Ranibizumab vs. Other Anti-VEGF Agents
CATT and IVAN: Rates were similar between the ranibizumab and bevacizumab groups
Study
Treatment Group
Aflibercept
0.5-mg
Bevacizumab
1.25-mg
Ranibizumab N %
IVAN
296 3%
314 4%
CATT
586
5.0%
599
4.7%
VIEW
601
3.8%
595
3.2%

51. 2 Year APTC Event Rates in AMD Studies Comparing Ranibizumab vs
2 Year APTC Event Rates in AMD Studies Comparing Ranibizumab vs. Other Anti-VEGF Agents
VIEW: Rates were similar between the ranibizumab and aflibercept groups
Study
Treatment Group
Aflibercept
0.5-mg
Bevacizumab
1.25-mg
Ranibizumab N %
IVAN
296 3%
314 4%
CATT
586
5.0%
599
4.7%
VIEW
601
3.8%
595
3.2%

52. Discussion
The 12% rate of APTC events in ranibizumab participants in the current study appears to be an outlier relative to other trials, including DRCR.net Protocol I, where the percentage was 7% with high overlap in DRCR.net clinical centers.
Additionally, across multiple retinal diseases, a meta-analysis from Thulliez et al did not identify an increased risk of major cardiovascular or hemorrhagic events with ranibizumab compared with control.
The inconsistencies in the totality of evidence creates uncertainty as to whether there is a true increased risk of APTC events with ranibizumab at this time.
Thulliez M, Angoulvant D, Le Lez ML, et al. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132(11):

53. Conclusions
Vision gains (from baseline) at 2 years were seen in all 3 groups with ~half the number of injections, slightly decreased frequency of visits, and decreased amounts of laser in the 2nd year
Among eyes with better VA no differences in 2-year vision outcomes identified
Among eyes with worse baseline VA:
Aflibercept, on average, had superior 2-year VA outcomes compared with bevacizumab, although the difference was diminished
The VA difference between aflibercept and ranibizumab that was noted at 1 year had decreased at 2 years and was no longer statistically significant.
The implication of the increased rate of APTC events with ranibizumab found in the current study is uncertain due to inconsistency with prior trials, warranting continued evaluation

54. 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
Full protocol available on clinicalTrials.gov (NCT ) 55