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Cole Eye InstituteCole Eye Institute
Steroids For Retinal Vein OcclusionSteroids For Retinal Vein Occlusion
Rishi P. Singh, MDStaff Physician, Assistant Professor of Ophthalmology
Cleveland Clinic, Cleveland, Ohio
Cole Eye InstituteCole Eye Institute
Financial Disclosures
• Advisor, consultant, or research support:
• Genentech, Ophthotech Corp, RegeneronPharmaceuticals, Inc., ThromboGenics, Inc., Valeant, Alcon
• Will be discussing off label use of triamcinolone acetonidefor macular edema secondary to RVO
• Advisor, consultant, or research support:
• Genentech, Ophthotech Corp, RegeneronPharmaceuticals, Inc., ThromboGenics, Inc., Valeant, Alcon
• Will be discussing off label use of triamcinolone acetonidefor macular edema secondary to RVO
Cole Eye InstituteCole Eye Institute
Agenda
• Discuss the advancements in retinal vein occlusion therapy
• Highlight benefits and drawbacks of current treatments
• Focus on outcomes of recent clinical trials to guide management
• Discuss the advancements in retinal vein occlusion therapy
• Highlight benefits and drawbacks of current treatments
• Focus on outcomes of recent clinical trials to guide management
Cole Eye InstituteCole Eye Institute
VA 20/100
CRT 485
s/p 3 bevacizumabinjection
VA 20/100
CRT 649
65 yr, hypertension, decrease in VA for 2 y
Audience Response:1. Switch Drugs to another anti-VEGF2. Switch Drugs to Intravitreal Triamcinolone3. Switch Drugs to Ozurdex
Audience Response:1. Start with Avastin2. Start with Lucentis3. Start with Eylea4. Start with steroid5. Observation - natural history is good
2
Cole Eye InstituteCole Eye Institute
Retinal Vein Occlusion (RVO): Overview
• RVO: Blockage of veins carrying blood away from the retina
• RVO: Second most common cause of vision loss due to retinal vascular disorders1,2
• Incidence: ~180,000 new cases annually3
• Prevalence: 0.3 to 8.4 cases per 1000 persons (US population-based studies)4
• RVO: Blockage of veins carrying blood away from the retina
• RVO: Second most common cause of vision loss due to retinal vascular disorders1,2
• Incidence: ~180,000 new cases annually3
• Prevalence: 0.3 to 8.4 cases per 1000 persons (US population-based studies)4
1.6 1.7
6.8
10.8
15.
17.3
0.2.4.6.8.
10.12.14.16.18.20.
30-39 40-49 50-59 60-69 70-79 ≥80
Prev
alen
ce p
er 1
,000
Age (yrs)
1. Orth DH, Patz A. Surv Ophthalmol 1978; 22:357-76. 2. Branch Vein Occlusion Group. Arch Ophthalmol 1986; 104:34-41. 3. Klein R et al. Arch Ophthalmol 2008;126:513-18 (projection to US population). 4. Rogers S et al. Ophthalmology 2010;117:313-19.e1.
Cole Eye InstituteCole Eye InstituteCole Eye InstituteCole Eye Institute4
(Branch) BRVO (Central) CRVO
Above fundus photograph and FA image courtesy of Retina Consultants of Houston.
collateral vessels
lamina cribrosa
region posterior to lamina cribrosa
Pathophysiology of BRVO and CRVO
Cole Eye InstituteCole Eye Institute
Macular Edema
Pathogenesis of macular edema
Vasodilation Leukostasis
Diapedesis Vascular permeability
Inflammatory proteins
VEGF
Retinal Vein Occlusion
Retinal hypoxia-ischemia
Inflammatory MediatorsIL-1, TNF-alpha
Cole Eye InstituteCole Eye InstituteCole EyeCole Eye
Why macular edema?
Unique anatomy of the macula:
Extremely high cell count with increased metabolic activity
Potential reservoir for the accumulation of extravascular fluid due to the thickness and loose binding of inner connecting fibers in the outer plexiform layer
Central avascular zone creating a watershed arrangement between the choroidal and retinal circulation thus decreasing resorption of extracellular fluid.
Unique anatomy of the macula:
Extremely high cell count with increased metabolic activity
Potential reservoir for the accumulation of extravascular fluid due to the thickness and loose binding of inner connecting fibers in the outer plexiform layer
Central avascular zone creating a watershed arrangement between the choroidal and retinal circulation thus decreasing resorption of extracellular fluid.
3
Cole Eye InstituteCole Eye Institute
Macular Edema is a common cause for vision loss in Retinal Vein Occlusion
• Pathogenesis
• Involves release of cytokines mediating the angiogenic & inflammatory processes
• Dysregulation of endothelial tight junction proteins
• Increased vascular permeability & further release of inflammatory mediators including IL-1, TNF-alpha, VEGF and others
Angiogenic, inflammatory
mediators
PermeabilityMigrationAdhesion
Cole Eye InstituteCole Eye Institute
Macular Edema
Targets for Clinical Intervention
Vasodilation Leukostasis
Diapedesis Vascular permeability
Inflammatory proteins
VEGF
Retinal Vein Occlusion
Retinal hypoxia-ischemia
CorticosteroidsInflammatory Mediators
IL-1, TNF-alpha
LASERANTI-VEGF
Cole Eye InstituteCole Eye Institute
Evolution of Treatment Targeting Macular Edema in CRVO
*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46.
4Haller JA et al. Ophthalmology 2011;118:2453-60. 5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et al. Br J Ophthalmol.
2009; 93:452-6.
Grid Photocoagulation(BVOS and CVOS)1
1995
Laser therapy Established:Laser as SOC for BRVOObservation as SOC for
CRVO
Cole Eye InstituteCole Eye Institute
Drawbacks of BVOS and CVOS Trials
● No OCT determination of edema and response to treatment
● ETDRS visual acuity wasn’t used
● 90 days of waiting for natural history – was there a delayed response?
● No OCT determination of edema and response to treatment
● ETDRS visual acuity wasn’t used
● 90 days of waiting for natural history – was there a delayed response?
4
Cole Eye InstituteCole Eye Institute
Triamcinolone* acetonide injection (SCORE)2
Dexamethasone intravitreal implant
(GENEVA)3,4
Corticosteroids
2010
Grid Photocoagulation(BVOS and CVOS)1
1995
Laser therapy
*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46.
4Haller JA et al. Ophthalmology 2011;118:2453-60. 5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et al. Br J Ophthalmol.
2009; 93:452-6.
Evolution of Treatment Targeting Macular Edema in CRVO
Cole Eye InstituteCole Eye Institute
Evolution of Treatment Targeting Macular Edema in CRVO
2010 2012
EYLEA® (aflibercept) Injection (COPERNICUS/
GALILEO)7,8
Lucentis (ranibizumab)(BRAVO and CRUISE)
Triamcinolone* acetonide injection (SCORE)2
Dexamethasone intravitreal implant
(GENEVA)3,4
Corticosteroids
2010
Grid Photocoagulation(BVOS and CVOS)1
1995
Laser therapy Anti-VEGF InjectionsAnti-VEGF Injections
*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46. 4Haller JA et al. Ophthalmology 2011;118:2453-60.
5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et
al. Br J Ophthalmol. 2009; 93:452-6.
Cole Eye InstituteCole Eye Institute
CRUISE: Ranibizumab (RBZ) in the Management of Macular Edema Secondary to CRVO1,2
Me
an
ch
an
ge fr
om
ba
selin
e
BC
VA
(E
TD
RS
lett
ers
)
*Secondary endpoint. †P<0.01 vs sham. Earliest statistically significant group difference (P<0.01 vs sham) was at Day 7. Vertical bars are ±1 standard
error of the mean. The last-observation-carried-forward method was used to impute missing data. BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study.
MonthDay 0 to Month 6
Monthly TreatmentMonth 6 to 12
PRN Treatment
Sham/0.5 mg (n=130) LUCENTIS 0.5 mg (n=130)
-2
0
2
4
6
8
10
12
14
16
18
2 4 6 8 10 120 D7
+14.9†
+0.8
+13.9
+7.3
0
+12.2
Cole Eye InstituteCole Eye Institute
Ranibizumab
Sham (n=130)
0.3 mg (n=132)
0.5 mg (n=130)
Months since diagnosis, mean (SD) 2.9 (2.9) 3.6 (3.2) 3.3 (3.7)
<3 months, n (%) 80 (61.5) 68 (51.5) 74 (56.9)
≥3 months, n (%) 50 (38.5) 64 (48.5) 56 (43.1)
BCVA (ETDRS letters), mean (SD) 49.2 (14.7) 47.4 (14.8) 48.1 (14.6)
BCVA (Snellen equivalent), median 20/100 20/100 20/100
Central foveal thickness* (μm), mean (SD)
687.0 (237.6) 679.9 (242.4) 688.7 (253.1)
Study Eye Characteristics
*No. of subjects assessed was 129, 131, and 130 in the sham, 0.3 mg, and 0.5 mg groups, respectively. SD=standard deviation, BCVA=best-corrected visual acuity, ETDRS=Early Treatment Diabetic Retinopathy Study.
5
Cole Eye InstituteCole Eye Institute
LUCENTIS Treatment
LUCENTIS TreatmentSham/0.5 mg
(n=130)
LUCENTIS0.5 mg (n=130)
Mean number of injections/ patient*
Treatment period† (Day 0 to Month 6) 5.4 5.5
Observation period (Month 6 to 12) 3.7 3.3
Patients receiving first PRN injection at Month 6, n (%) 100 (76.9) 64 (49.2)
*During the 6-month treatment period sham patients received sham injections (Day 0, Months 1–5). During the 6-month observation period sham patients received PRN LUCENTIS 0.5 mg if they met retreatment criteria (Months 6–11).
†Based on Month 6 database. 6 total possible injections.PRN = pro re nata.
Cole Eye InstituteCole Eye Institute
HORIZON RVO: 1-Year Follow-Up of CRUISE Study1
+9.4+7.6
+16.2
+12.0
-5
0
5
10
15
20
0 3 6 9 12 15 18 21 24
Mean Change from CRUISE Baseline, ETDRS Letters
Sham/0.5 mg RBZ 0.5 mg RBZ
CRUISE HORIZON RVO
-4.2
-4.1
-7
-6
-5
-4
-3
-2
-1
0
12 15 18 21 24
Months
Mean Change from HORIZON Baseline, ETDRS Letters
Sham/0.5 mg RBZ 0.5 mg RBZ
1Heier JS et al.Ophthalmology 2012;119:802-9.
Months
Cole Eye InstituteCole Eye Institute
Potential AEs of anti-VEGF treatment in patients
Ocular AEs
Vitreous hemorrhage
Vitreomacular traction
RPE tears
Retinal detachment
Elevated intraocular pressure
Intraocular inflammation
Endophthalmitis
Systemic AEs
Hypertension
Proteinuria
Impairment of wound healing
Arterial thromboembolic events
Myocardial infarctions
Stroke
Dyspnea
Cole Eye InstituteCole Eye Institute
Conclusions from CRUISE and HORIZON studies:Limitations of anti-VEGF treatment
● Macular hypoxia is not alleviated with anti-VEGF
● Requires multiple injections over extended periods (average 8-9 injections over 12 months).
● If you inject less frequently you can lose vision.
● Not all people gain vision
● Some people lose vision
● Side effects are low but not zero
● Macular hypoxia is not alleviated with anti-VEGF
● Requires multiple injections over extended periods (average 8-9 injections over 12 months).
● If you inject less frequently you can lose vision.
● Not all people gain vision
● Some people lose vision
● Side effects are low but not zero
6
Cole Eye InstituteCole Eye Institute
More data to consider.....
Cole Eye InstituteCole Eye Institute
Bhisitkul: Predictive value in RVO of early vs late or incomplete ranibizumab response defined by OCT
• Design: Post hoc analysis from the 2 prospective, randomized, controlled clinical trials of BRAVO and CRUISE
• Participants: 397 from BRAVO, 392 from CRUISE
• Methods: Time-domain OCT imaging data were analyzed
• Main Outcome Measure: Mean change from baseline BCVA letter score at month 6 and 12
• Design: Post hoc analysis from the 2 prospective, randomized, controlled clinical trials of BRAVO and CRUISE
• Participants: 397 from BRAVO, 392 from CRUISE
• Methods: Time-domain OCT imaging data were analyzed
• Main Outcome Measure: Mean change from baseline BCVA letter score at month 6 and 12
Cole Eye InstituteCole Eye Institute
Study Design
• Patients in each study were classified according to their OCT characteristics at baseline into 3 groups• CFT ≤250 µm• Intraretinal cysts of fluids (CME)• Subretinal fluid (SRF)
• Patients were assessed for the effect of ranibizumab on these OCT parameters as well as on their visual acuity outcome at 6 and 12 months
• Patients in each study were classified according to their OCT characteristics at baseline into 3 groups• CFT ≤250 µm• Intraretinal cysts of fluids (CME)• Subretinal fluid (SRF)
• Patients were assessed for the effect of ranibizumab on these OCT parameters as well as on their visual acuity outcome at 6 and 12 months
Cole Eye InstituteCole Eye Institute
Early vs Late or Incomplete Ranibizumab Responders in BRVO and CRVO Studies
Delayed OCT response means worse visual outcomes
BRAVO CRUISE
7
Cole Eye InstituteCole Eye Institute
Effect of Ranibizumab on CME in BRVO and CRVO Studies
Many patient had CME despite therapy
If CME was present at Month 3, outcomes
were worse
Cole Eye InstituteCole Eye Institute
Evolution of Treatment Targeting Macular Edema in CRVO
2010 2012
EYLEA® (aflibercept) Injection (COPERNICUS/
GALILEO)7,8
Lucentis (ranibizumab)(BRAVO and CRUISE)
Triamcinolone* acetonide injection (SCORE)2
Dexamethasone intravitreal implant
(GENEVA)3,4
Corticosteroids
2010
Grid Photocoagulation(BVOS and CVOS)1
1995
Laser therapy Anti-VEGF InjectionsAnti-VEGF Injections
*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46. 4Haller JA et al. Ophthalmology 2011;118:2453-60.
5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et
al. Br J Ophthalmol. 2009; 93:452-6.
Cole Eye InstituteCole Eye Institute
Primary Results: The Standard Care versus COrticosteroid
for REtinal Vein Occlusion Study(The SCORE Study)
SCORE Study Research Group
Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human
Services(Funded by NEI 2003)
Cole Eye InstituteCole Eye Institute
Retreat at 4 month intervals
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.
SCORE Study Design
● Patients randomized to
● 1 mg steroid
● 4 mg steroid
● SOC treatment – BRVO grid laser, CRVO nothing
● Patients randomized to
● 1 mg steroid
● 4 mg steroid
● SOC treatment – BRVO grid laser, CRVO nothing
8
Cole Eye InstituteCole Eye Institute
SCORE BRVOChange in Visual Acuity
SCORE BRVOChange in Visual Acuity
M4 M8 M16 M20 M24 M28 M32 M36M12
BRVO Trial
After month 12 and through month 36, mean VA improvement was greatest in the SC group. Cole Eye InstituteCole Eye Institute
SCORE: BRVOMonth 12 Safety Outcomes
Outcome Grid Laser
1 mgSteroid
4 mgSteroid
IOP-lowering meds 2% 8% 41%
Cataract progression
13% 25% 35%
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.
Cole Eye InstituteCole Eye Institute
SCORE: BRVO Conclusions
● No difference in visual acuity outcomes at month 12 between standard care (grid laser) and triamcinolone groups
● Rate of adverse events (IOP elevation, cataract progression) were highest in 4-mg triamcinolone group
● Grid laser recommended over intravitreal triamcinolone for patients with macular edema due to BRVO
● No difference in visual acuity outcomes at month 12 between standard care (grid laser) and triamcinolone groups
● Rate of adverse events (IOP elevation, cataract progression) were highest in 4-mg triamcinolone group
● Grid laser recommended over intravitreal triamcinolone for patients with macular edema due to BRVO
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.
Cole Eye InstituteCole Eye Institute
SCORE: CRVO: Month 12 Visual Acuity Outcomes
VisionOutcome
Observation1 mg
Steroid4 mg
Steroid
≥15 letters 6.8% 26.5% 25.6%
Mean letter
change
-12.1 -1.2 -1.2
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.
9
Cole Eye InstituteCole Eye Institute
SCORE: CRVO: Month 12 Safety Outcomes
Outcome Observation1 mg
Steroid4 mg
Steroid
IOP-lowering meds 8% 20% 35%
Cataract progression
18% 26% 33%
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145. Cole Eye InstituteCole Eye Institute
SCORE: CRVO Conclusions
● Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema
● 1-mg triamcinolone dose has fewer ocular adverse events than the 4-mg dose
● Treatment with 1 mg triamcinolone for up to 1 year should be considered in eyes with vision loss associated with macular edema in CRVO
● Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema
● 1-mg triamcinolone dose has fewer ocular adverse events than the 4-mg dose
● Treatment with 1 mg triamcinolone for up to 1 year should be considered in eyes with vision loss associated with macular edema in CRVO
SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.
Cole Eye InstituteCole Eye Institute
OZURDEX™ RVO DataDexamethasone intravitreal implant in patients with
vision loss due to macular edema associated with retinal vein occlusion
OZURDEX™ RVO DataDexamethasone intravitreal implant in patients with
vision loss due to macular edema associated with retinal vein occlusion
Two identical, 6-month, randomized, prospective, multicenter, masked, sham-controlled, parallel-group, phase 3 clinical
trials
Primary endpoint in the pooled analysis was time to ≥ 15 letter gain of the 2 identically designed studies
Cole Eye InstituteCole Eye Institute
1267 Patients randomized1:1:1
DEX 350412 1st injection
Completed day 180396 patients
DEX 700421 1st injection
Sham Procedure423 sham injection
Completed day 180401 patients
Completed day 180399 patients
Discontinued prior to day 36014 patients
Discontinued prior to day 36013 patients
Discontinued prior to day 36011 patients
Completed day 360316 patients
Completed day 360330 patients
Completed day 360313 patients
DEX 350/700329 OL injection
DEX 700/700341 OL injection
Sham/DEX 700327 OL injection
GENEVA Study: Trial Design and Patient Disposition 6-Month Study with 6-Month Open-Label Follow-up
6-Month Open-Label Extension997 patients rolled over to receive DEX 700 µg *
OL = open label* 199 patients did not receive an open-label injection
11 patients no injection
10
Cole Eye InstituteCole Eye Institute
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lativ
e R
esp
on
se R
ate
(%
)
GENEVA Trial: Best Corrected Visual Acuity: Time to the First Gain of ≥ 15 Letters – Kaplan-Meier Analysis
P < .001
Days from the First Dose
Sham (n = 426)
Dexamethasone-DDS 350 µg (n = 414)
Dexamethasone-DDS 700 µg (n = 427)DEX 700 vs Sham: <.001DEX 350 vs Sham: <.001
0 20 40 60 80 100 120 140 160 180
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Demographic and Baseline Characteristics
DEX Implant 0.7 mgn=427
DEX Implant 0.35 mgn=414
Sham n=426
Sex (female) 49.2% 46.9% 43.7%
Race (white) 75.2% 75.4% 74.6%
Mean age (years)(range)
64.7(33-90)
64.9(31-96)
63.9(31-91)
Mean VA (letters)(range)
54.3 (20/80)(34-68)
53.9 (20/80)(31-79)
54.8 (20/80)(28-80)
Mean OCT (µm)(range)
562(127-1320)
555(116-1369)
539(94-1218)
Diagnosis in study eye
CRVO 31.9% 37.2% 34.5%BRVO 68.1% 62.8% 65.5%
Duration of ME (days)< 90 16.4% 18.4% 15.3%90-179 51.3% 52.7% 51.6%> 180 32.3% 29.0% 33.1%
Haller J, et al. Ophthalmology. 2010;117:1134-1146.
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Patients With BCVA Improvement of≥15 Letters From Baseline
21.3
29.3
21.8 21.5
17.9
28.5
23.4
19.3
7.5
11.313.1
17.6
0
5
10
15
20
25
30
35
Day 30 Day 60 Day 90 Day 180
Pe
rce
nta
ge
of
Pa
tie
nts
Sham (n = 426)
Dexamethasone-DDS 350 µg (n = 414)Dexamethasone-DDS 700 µg (n = 427)
Study Day
P < .001
P < .001
P < .001
P values are for Dexamethasone-DDS 700 µg vs Sham(136 – 210 Days)
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Post-implant visit window varied considerably
Actual visits 136 to ≤180 days >180 to ≤200 days >200 days
Sham 203 (50.6%) 181 (45.1%) 17 (4.2%)
700 μg 188 (46.2%) 203 (49.9%) 16 (3.9%)
Per protocol specification
76–135 days
Day 90
46–75 days19–45 daysVisit window in days from implant
insertion
Day 60Day 30 Day 180
136–210 days
11
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Patients With BCVA Improvement of ≥15 Letters From Baseline (excluding visits beyond 180 days)
26.4
21.3
29.3
21.8
19.417.9
28.5
23.4
17.0
7.5
11.3
13.1
0
5
10
15
20
25
30
35
Day 30 Day 60 Day 90 Day 180
Pe
rcen
tag
e o
f P
ati
en
ts
Sham
Dexamethasone-DDS 350 µg Dexamethasone-DDS 700 µg
Study Day
P < .001
P < .001
P < .001
P values are for Dexamethasone-DDS 700 µg vs Sham
(n = 208)
(n = 216)
(n = 229)
(n = 427)
(n = 414)
(n = 426)
(n = 427)(n = 414)
(n = 426)
(n = 427)(n = 414)
(n = 426)
P < .017
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Mean Change in BCVA From Baseline Retreated Populations
Study Day
**
*
**
*
AllTreated
with DEX 700
P < .05 for DEX 700/700 vs Sham/700
0
2
4
6
8
10
12
14
Baseline Day 30 IT Day 60 IT Day 90 IT Day 120 IT Day 150 IT Day 180 IT Day 30 OL Day 60 OL Day 90 OL Day 120 OL Day 150 OL Day 180 OL
Mea
n B
CV
A Im
pro
vem
ent L
ette
rs
Dex 700/700 (n=341)Dex 350/700 (n=329)
Sham/700 (n=327)
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Mean BCVA improvement in BRVO & CRVO
-3
0
3
6
9
12
Baseline Day 30 Day 60 Day 90 Day 150 Day 180
0.7 mg (n=136)Sham (n=147)
CRVO
NS
P<0.001
P<0.001P<0.001
0
3
6
9
12
Baseline Day 30 Day 60 Day 90 Day 150 Day 180
0.7 mg (n=291)Sham (n=279)
BRVO P<0.001P<0.001
P<0.001P=0.008
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% of Patients withIOP ≥ 35 m`mHg
% of Patients withIOP ≥ 25 mmHg
% of Patients with≥10 mmHg Change
from Baseline
GENEVA Trial: Changes in IOP Over 12 Months No increased IOP response following 2nd
Injection
12
Cole Eye InstituteCole Eye Institute
GENEVA Trial: Selected Ocular Adverse Events at 12 Months
● Cataract extractions
● Study Eye
● DEX 700/700, n=4 (1.2%)
● DEX 350/700, n=5 (1.5%)
● Non-Study Eye
● DEX 700/700, n=1 (0.3%)
● DEX 350/700, n=2 (0.6%)
● Sham/DEX 700, n=2 (0.6%)
● Cataract extractions
● Study Eye
● DEX 700/700, n=4 (1.2%)
● DEX 350/700, n=5 (1.5%)
● Non-Study Eye
● DEX 700/700, n=1 (0.3%)
● DEX 350/700, n=2 (0.6%)
● Sham/DEX 700, n=2 (0.6%)
● IOP procedures
● Study Eye
● DEX 700/700, n=4 (1.2%)
● DEX 350/700, n=2 (0.6%)
● Sham/DEX 700, n=1 (0.3%)
● IOP procedures
● Study Eye
● DEX 700/700, n=4 (1.2%)
● DEX 350/700, n=2 (0.6%)
● Sham/DEX 700, n=1 (0.3%)
Cole Eye InstituteCole Eye Institute
But what is real life experience with Ozurdex?
Cole Eye InstituteCole Eye Institute
Retrospective Study of Two or MoreDexamethasone Intravitreal Implant 0.7 mg
Injections for Retinal Vein Occlusion
SHASTA Study
Antonio Capone, Jr., MD1; Michael Singer, MD2; David Dodwell, MD3; Richard Dryer, MD4; Kean Oh, MD5; John Walt, MBA6; Lanita C Scott, MD6; David A Hollander, MD,
MBA6
Antonio Capone, Jr., MD1; Michael Singer, MD2; David Dodwell, MD3; Richard Dryer, MD4; Kean Oh, MD5; John Walt, MBA6; Lanita C Scott, MD6; David A Hollander, MD,
MBA6
1Associated Retinal Consultants P.C., Novi, MI; 2Medical Center Ophthalmology Associates, San Antonio, TX; 3Illinios Retina Center, Springfield, IL; 4Retina Northwest P.C., Portland OR; 5Associated Retinal Consultants P.C., Traverse City, MI;
6Allergan, Inc. Irvine, CA
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SHASTA Study: Purpose of Study
● To evaluate Dexamethasone Intravitreal Implant 0.7 mg (Ozurdex®) in the treatment of macular edema (ME) due to retinal vein occlusion (RVO) in patients receiving ≥2 Injections
● Safety
● Efficacy
● Reinjection interval
● To evaluate Dexamethasone Intravitreal Implant 0.7 mg (Ozurdex®) in the treatment of macular edema (ME) due to retinal vein occlusion (RVO) in patients receiving ≥2 Injections
● Safety
● Efficacy
● Reinjection interval
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Study Design
● Retrospective, multicenter (26 sites) chart review
● Included were patients with ≥2 injections of Ozurdex®
● Additional RVO treatments were allowed
● Only 1 eye (most Ozurdex® injections) was included
● Data were collected from patient charts from the first Ozurdex® injection and included each subsequent visit through a minimumof 3 months and up to 6 months after the last Ozurdex® injection
● Retrospective, multicenter (26 sites) chart review
● Included were patients with ≥2 injections of Ozurdex®
● Additional RVO treatments were allowed
● Only 1 eye (most Ozurdex® injections) was included
● Data were collected from patient charts from the first Ozurdex® injection and included each subsequent visit through a minimumof 3 months and up to 6 months after the last Ozurdex® injection
Capone, Jr. et al. Retina. 2013Capone, Jr. et al. Retina. 2013Cole Eye InstituteCole Eye Institute
SHASTA Study: Patient Eligibility
● Inclusion Criteria
● At least 18 years of age
● Macular edema in the study eye due to BRVO or CRVO
● Patient had received ≥2 Ozurdex® in the study eye and had follow-up dataa minimum of 3 months after the latest injection
● Exclusion Criteria
● Received Ozurdex® as part of, or during, a clinical study
● Enrollment of the fellow eye in the study
● Inclusion Criteria
● At least 18 years of age
● Macular edema in the study eye due to BRVO or CRVO
● Patient had received ≥2 Ozurdex® in the study eye and had follow-up dataa minimum of 3 months after the latest injection
● Exclusion Criteria
● Received Ozurdex® as part of, or during, a clinical study
● Enrollment of the fellow eye in the study
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SHASTA Study: Outcome Measures
● Primary Efficacy Endpoints
● Change in BCVA from baseline 4 to 20 weeks following last injection
● Secondary Efficacy Endpoints
● Change in BCVA from baseline following each injection
● Percent of patients with ≥2 lines increase in BCVA from baseline
● Percent of patients with ≥3 lines increase in BCVA from baseline
● Change from baseline in central retinal thickness (CRT) by OCT
● Safety Measures
● Included adverse events, IOP, and ocular surgeries
● Primary Efficacy Endpoints
● Change in BCVA from baseline 4 to 20 weeks following last injection
● Secondary Efficacy Endpoints
● Change in BCVA from baseline following each injection
● Percent of patients with ≥2 lines increase in BCVA from baseline
● Percent of patients with ≥3 lines increase in BCVA from baseline
● Change from baseline in central retinal thickness (CRT) by OCT
● Safety Measures
● Included adverse events, IOP, and ocular surgeries
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SHASTA Study: Demographics
Factor All PatientsN = 289
BRVO PatientsN = 157
CRVO PatientsN = 132
Age in YearsMean (SD) 71.9 (11.0) 72.2 (11.2) 71.6 (10.7)Range 39-94 39–94 39–91
Sex, n (%)Female 166 (57.4%) 92 (58.6%) 74 (56.1%)Male 123 (42.6%) 65 (41.4%) 58 (43.9%)
Diagnosis in Study EyeBRVO 157 (54.3%) – –CRVO 132 (45.7%) – –
RaceWhite 142 (49.1%) 67 (42.7%) 75 (56.8%)Black or African American 9 (3.1%) 6 (3.8%) 3 (2.3%)Asian 7 (2.4%) 6 (3.8%) 1 (0.8%)Pacific Islander 1 (0.3%) 0 (0.0%) 1 (0.8%)Not Recorded 130 (45.0%) 78 (49.7%) 52 (39.4%)
EthnicityHispanic or Latino 10 (3.5%) 8 (5.1%) 2 (1.5%)Not Hispanic or Latino 137 (47.4%) 65 (41.4%) 72 (54.5%)Not Recorded 142 (49.1%) 85 (53.5%) 58 (43.9%)
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SHASTA Study: Baseline Characteristics
Factor All PatientsN = 289
BRVO PatientsN = 157
CRVO PatientsN = 132
Lens Status in Study Eye, n (%)Phakic 128 (44.3%) 69 (43.9%) 59 (44.7%)Pseudophakic 158 (54.7%) 86 (54.8%) 72 (54.5%)Not Recorded 3 (1.0%) 2 (1.3%) 1 (0.8%)
Ischemia in Study EyeYes 88 (30.4%) 55 (35.0%) 33 (25.0%)No 193 (66.8%) 97 (61.8%) 96 (72.7%)Unknown 6 (2.1%) 4 (2.5%) 2 (1.5%)Not Recorded 2 (0.7%) 1 (0.6%) 1 (0.8%)
History of IOP Response to SteroidYes 45 (15.6%) 22 (14.0%) 23 (17.4%)No 168 (58.1%) 92 (58.6%) 76 (57.6%)Not Recorded 76 (26.3%) 43 (27.4%) 33 (25.0%)
Glaucoma or Ocular Hypertension 91 (31.5%) 44 (28.0%) 47 (35.6%)
None or Not Recorded in Chart 198 (68.5%) 113 (72.0%) 85 (64.4%)Baseline IOP-Lowering MedicationYes 70 (24.2%) 35 (22.3%) 35 (26.5%)No 21 (7.3%) 9 (5.7%) 12 (9.1%)Not Recorded 198 (68.5%) 113 (72.0%) 85 (64.4%)
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SHASTA Study: Baseline Characteristics
Factor All PatientsN = 289
BRVO PatientsN = 157
CRVO PatientsN = 132
Duration of RVO at Time of First Ozurdex Implant Injection (Months)
Mean (SD) 18.4 (23.4) 20.1 (25.0) 16.4 (21.3)
Range 0–150.2 0–119.1 0–150.2
Mean (SD) Best-CorrectedVisual Acuity in the Study Eye (lines)
9.8 (4.6)(Snellen 20/100)
11.0 (4.3)(Snellen 20/80)
8.4 (4.7)(Snellen 20/160)
Mean (SD) Central Retinal Thickness, μm 438 (182) 413 (149) 469 (201)
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Treatment Prior to 1st Ozurdex® No. of Patients %
Baseline Treatments/Procedures* 248 86%
Anti-VEGF Treatment (Intravitreal) 205 71%
Avastin 181 63%
Lucentis 40 14%
Macugen 3 1%
Triamcinolone (Intravitreal) 115 40%
Treatment Prior to 1st Ozurdex® No. of Patients %
Any Laser Treatment 112 39%
Focal Laser 85 29%
Panretinal Photocoagulation 45 16%
Pars Plana Vitrectomy 37 13%
No Baseline Treatment or Procedure for RVO 39 14%
* Patients may have received >1 type of additional treatment* Patients may have received >1 type of additional treatment
SHASTA Study: Treatments Pre Ozurdex
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Number ofOzurdex®
TreatmentsN %
2 119 41%
3 80 28%
4 36 12%
5 32 11%
6 12 4%
7 5 2%
8 3 1%
9 2 1%
SHASTA Study: Number of Ozurdex® Treatments
All PatientsMean (SD) 3.2 (1.5)
Injections
BRVOMean 3.2 (1.4) Injections
CRVOMean 3.2 (1.5) Injections
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* Based on the mean number of days between injections for each patient* Based on the mean number of days between injections for each patient
Mean Time Between Ozurdex® Injections*
Time(Months)
Number ofPatients %
1 0 0%
2 0 0%
3 25 9%
4 86 30%
5 73 25%
6 39 14%
>6 66 23%
Mean (SD) 169 (74) Days = 5.6 Months
Median 150 Days = 4.9 Months
Range 81-527 Days
91% had their next injection at 4 months and beyond
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* P≤.037; Error bars represent SD* P≤.037; Error bars represent SD
SHASTA Study: Change in BCVA (Lines) from Baseline at 4−20 Weeks After Each Injection
N = 283 N = 276 N = 268 N = 143 N = 76 N = 39 N = 18Baseline
Mean peak change 4−20 weeks a er final Ozurdex® was an improvement of 1.0 (3.5 SD) line (5 ETDRS Letters)
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7 injections: 83.3% (5/6 patients)8 injections: 100.0% (3/3 patients)9 injections: 100.0% (1/1 patient)
7 injections: 83.3% (5/6 patients)8 injections: 100.0% (3/3 patients)9 injections: 100.0% (1/1 patient)
Percentage of Patients with ≥2 LinesImprovement After Each Injection
N = 283 N = 275 N = 148 N = 79 N = 39 N = 18
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7 injections: 83.3% (5/6 patients)8 injections: 66.7% (2/3 patients)9 injections: 100.0% (1/1 patient)
7 injections: 83.3% (5/6 patients)8 injections: 66.7% (2/3 patients)9 injections: 100.0% (1/1 patient)
Percentage of Patients with ≥3 LinesImprovement After Each Injection
N = 283 N = 275 N = 148 N = 79 N = 39 N = 18
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2 Lines or More Improvement BRVO CRVO
Percent Overall 59.7% 66.7%
N 92 86
Range After Injections* 46.8–55.6% 26.3–55.6%
* Percent of patients after the first through sixth injections (range)* Percent of patients after the first through sixth injections (range)
SHASTA Study: Overall 2−3 Lines Improvement BRVO vs. CRVO
All Patients
Improvement Percent Overall N Range After Injections*
2 Lines or More 62.9% 178 38.5–55.6%
3 Lines or More 48.1% 136 30.4–50.0%
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Change in CRT from Baseline After Each Injection
* P≤.002; Error bars represent SD* P≤.002; Error bars represent SD
SHASTA Study: Change in CRT from Baseline After Each Injection
BaselineN = 247 N = 247 N = 236 N = 133 N = 70 N = 33 N = 15
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SHASTA Study: CRT ≤250 Microns
CRT All Patients BRVO CRVO
≤250 µm 65.3% 66.0% 64.4%
N 188/288 103/156 85/132
Measurements were by spectral and/or time‐domain OCT
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Treatment Post 1st Ozurdex® No. of Patients %
Treatments/Procedures Other Than Ozurdex* 205 71%
Anti-VEGF Treatment (Intravitreal) 186 64%
Avastin 127 44%
Lucentis 94 33%
Macugen 0 0%
Triamcinolone (Intravitreal) 9 3%
* Patients may have received >1 type of additional treatment* Patients may have received >1 type of additional treatment
SHASTA Study: Treatments Post Ozurdex
Treatment Post 1st Ozurdex® No. of Patients %
No Study Treatments in Addition to Ozurdex* 84 29%
Any Laser Treatment 72 25%
Focal Laser 54 19%
Panretinal Photocoagulation 27 9%
Pars Plana Vitrectomy 3 1%
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SHASTA Study: Time Between First Ozurdex® Injection and Next Anti-VEGF Injection
Time to Anti-VEGF InjectionTotal (N=186) %
Days Months
≤30 ~1 Month 11 5.9%
31–60 ~2 Months 12 6.5%
61–90 ~3 Months 12 6.5%
91–120 ~4 Months 45 24.2%
121–150 ~5 Months 23 12.4%
151–180 ~6 Months 9 4.8%
>180 ~6+ Months 74 39.8%
80% had an anti-VEGF 3 months and beyond40% lasted 6 months or more without an anti-VEGF injection
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SHASTA Study: Ozurdex® Safety
● IOP increases and cataract progression were the only treatment-related adverse events with an incidence of 2% or higher
● IOP increases and cataract progression were the only treatment-related adverse events with an incidence of 2% or higher
There was 1 report of endophthalmitis during the study
There were no deaths and no serious adverse events relatedto treatment
Outcome N
Cataract Surgery During the Study 46
Lens Opacity at Baseline 39/46 (85%)
Grade 2 or 3 Lens Opacity at Baseline 28/46 (61%)
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SHASTA Study: IOP Safety
Outcome N %
Glaucoma Surgery (Laser or Incisional) 9 3.1%
Glaucoma Laser Surgery 4 1.4%
Glaucoma Incisional Surgery 5 1.7%
IOP-lowering Medications Initiated Secondary to Ozurdex 109 38%
IOP at Any Point During Study
Change ≥10 mm Hg from Baseline 91 32.6%
Recorded ≥25 mm Hg at Any Visit 97 33.7%
Recorded ≥35 mm Hg at Any Visit 27 9.4%
IOP at Final Study Visit
Change ≥10 mm Hg from Baseline 12 4.3%
Recorded ≥25 mm Hg at Final Visit 14 4.9%
Recorded ≥35 mm Hg at Final Visit 5 1.8%
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Summary of SHASTA Study
● 63% of patients had vision improve by 2 or more lines
● Average OCT improved approximately 200 µm with each injection
● 69% of patients required an Ozurdex® between 4-6 months
● 80% did not need an anti-VEGF within 3 months after the injection
● At baseline, 31.5% of patients had glaucoma/OHT, 15.6% had a history of IOP response to steroids, yet <5% of patients had clinically elevated IOP at their final visit
● 63% of patients had vision improve by 2 or more lines
● Average OCT improved approximately 200 µm with each injection
● 69% of patients required an Ozurdex® between 4-6 months
● 80% did not need an anti-VEGF within 3 months after the injection
● At baseline, 31.5% of patients had glaucoma/OHT, 15.6% had a history of IOP response to steroids, yet <5% of patients had clinically elevated IOP at their final visit
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SHASTA Study: Conclusions
• Clinical use of 2 or more dexamethasone implants, either alone or in combination with anti-VEGF treatments, is safe and effective in the treatment of macular edema following RVO if IOP increases are monitored and treated
• Decreases in macular edema and improvements in visual acuity were maintained with ongoing dexamethasone implant treatment
• No new safety concerns developed after the use of multiple implants
• There was no evidence of a cumulative effect of repeat dexamethasone implants on IOP
• Clinical use of 2 or more dexamethasone implants, either alone or in combination with anti-VEGF treatments, is safe and effective in the treatment of macular edema following RVO if IOP increases are monitored and treated
• Decreases in macular edema and improvements in visual acuity were maintained with ongoing dexamethasone implant treatment
• No new safety concerns developed after the use of multiple implants
• There was no evidence of a cumulative effect of repeat dexamethasone implants on IOP
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RVO Considerations
● Which is more important:
● Efficacy?
● Cost?
● Convenience?
● Risks?
● Which is more important:
● Efficacy?
● Cost?
● Convenience?
● Risks?
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RVO Conclusions
● Consider treatment with multimodalities:
● Gain benefits of each and reduces side effects of both
● Potentially helps improve outcomes
● Consider treatment with multimodalities:
● Gain benefits of each and reduces side effects of both
● Potentially helps improve outcomes
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Evaluation of Therapies for CRVO
● Can a corticosteroid “rescue” eyes that are failing anti-VEGF therapy with aflibercept?
● Can anti-VEGF therapy with aflibercept “rescue” eyes that are failing treatment with bevacizumab?
● Can a corticosteroid “rescue” eyes that are failing anti-VEGF therapy with aflibercept?
● Can anti-VEGF therapy with aflibercept “rescue” eyes that are failing treatment with bevacizumab?
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Study of COmparative Treatments
in REtinal Vein Occlusion 2 (SCORE2)
Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services
Grants: 1U10EY023533 -01, 1U10EY023529-01, 1U10EY023521-01
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SCORE2: Current 2-Arm Design
R=1:1 RandomizationStatus assessment at Month 6 when
primary noninferiority outcome is assessed
Disposition after Month 6: Secondary outcomes measured at Month 12
Baseline
Aflibercept: Monthly injections through Month 5
Bevacizumab: Monthly injections through Month 5
Good response
Poor or marginal response
Good response
Poor or marginal response
R
R
R
Aflibercept monthly: Months 6-11
Aflibercept TAE**: Months 6-11
Dexamethasone implant @ M6, PRN @ M9, M10, M11
Bevacizumab monthly: Months 6-11
Bevacizumab TAE**: Months 6-11
Aflibercept monthly: M6, M7, M8 and TAE**
* Poor or marginal response: (1) Visual acuity letter score less than 58/less than 20/80) OR visual acuity letter score improvement of ≤5 from baseline (ie, Month 6 visual acuity letter score – Baseline visual acuity score <5 letter). [Note that at least some of the visual acuity deficit is attributed, by the investigator,
to macular edema secondary to CRVO] AND (2) OCT has 1 or more of the following: central subfield thickness of ≥300 µm on SD-OC-OCT (or ≥320 µm if measured on Heidelberg Spectralis Machine), presence of intraretinal cystoid spaces, subretinal fluid.
Good response: Otherwise
** TAE = Treatment and extend with 2-week extension increments
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Back to our case
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65 yr, hypertension, decrease in VA for 2 y
VA 20/100
CRT 485
s/p 3 bevacizumabinjection
VA 20/100
CRT 649
Audience Response:1. Switch Drugs to another anti-VEGF2. Switch Drugs to Intravitreal Triamcinolone3. Switch Drugs to Ozurdex
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s/p 8 bevacizumabinjections VA 20/100
CRT 446
7 m post Ozurdex
VA 20/50 CRT 269
VA 20/100
CRT 485
s/p 3 bevacizumabinjection
VA 20/100
CRT 649
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Thank You