RVO management different studies.

1. APPROACH TO TREATING
RVO
Dr. Shalini Kumari

2.  Retinal vein occlusion (RVO) is the second most
common retinal vascular disease after diabetic
retinopathy.

3. prevalence

4. Worldwide prevalence
 approximately 16.4 million adults are affected by
RVO:
 13.9 million by BRVO
 and 2.5 million by CRVO
 Rogers S, McIntosh RL, Cheung N, et al; International Disease Consortium. The prevalence of retinal vein occlusion: pooled data
from population studies in the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117(2):313-319 e1

5. Natural course
 50-60% patients: recovery of visual acuity to
20/40, or better, without therapy.
 91% within 1st
year
 Pre-treatment VA
 Depends on site and degree of occlusion
 collateral circulation
 Poor prognosis
 Chronic macular edema (14% VA>6/12)
 Vit h’ge due to neovascularization

6. Management of BRVO
 GENERAL PRINCIPALS
 Maximise Recovery and Vision
 Prevent re-occlusion
 Detect any associated systemic disease
 Detect / Prevent Glaucoma
 Protect other eye
 Exclusion / control of
 Diabetes
 HTN
 hyperlipidaemia
 hyperviscosity/coagulation states
 antiphospholipid syndrome

7. Blood investigations
 Thrombophilic conditions, such as the following, may also be
involved:
 Homocysteine levels
 Protein S deficiency
 Protein C deficiency
 Resistance to activated protein C (factor V Leiden)
 Antithrombin III deficiency
 Antiphospholipid antibody

8. DIAGNOSTIC EVALUATION
Fluorescein Angiography –
• to identify areas of nonperfusion
• to identify areas of leakage
OCT
• to monitor macular edema

9. TREATMENT of BRVO
1. Medical
2. LASER
3. Surgical

10. BVOS (1984)
 Purpose
To determine
 whether scatter argon laser photocoagulation can prevent
the development of neovascularization.
 whether peripheral scatter argon laser photocoagulation
can prevent vitreous hemorrhage.
 whether macular argon laser photocoagulation can
improve visual acuity in eyes with macular oedema
reducing vision to 20/40 or worse.

11. Eligibility criteria
 Fluorescein-proven perfused macular edema
involving the foveal center,
 Recent BRVO (3–18 months’ duration),
 BCVA of 20/40 or worse

12.  TREATMENT GROUPS: Photocoagulation vs.
Observation
 RESULTS:
IMPACT: Established macular laser photocoagulation as the
clinical standard therapy for macular edema due to BRVO

13. Recommendations (BVOS)
 Observation for 3months to allow for resolution of macular edema
and haemorrhages
 If VA ≤ 20/40 and persistent macular edema FFA to
determine the extent of ischemia
 In the absence of macular ischemia , laser grid photocoagulation to
the area of leakage

14. Treatment of Neovasularization in BVOS
 If peripheral scatter laser photocoagulation is applied in eyes with
large areas of nonperfusion, the incidence of neovascularization can be
reduced from about 40% to 20%.
 In prophylactic treatment , many eyes (60%) that would never develop
neovascularization would receive peripheral scatter laser.
 Only CNP, follow up at 4 monthly intervals (no laser)
 In confirmed neovascularization by FFA, PROMPT peripheral scatter
laser can reduce the likelihood of vitreous hemorrhage from 60% to
30%.

15. SCATTER PHOTOCOAGULATION PROCEDURE
 Blue green laser
 Size : 200- 500 micron
 Number: cover entire areas of capillary non
perfusion as defined by FFA
 Placement : 1 burn width apart ( no closer than 2D
diameters from center of fovea & extending
peripherally at least to equator

16. SCATTER
LASER

17. GRID PHOTOCOAGULATION PROCEDURE
 Size: 50 to 100 μm
 Exposure: 0.05 to 0.1 seconds
 Intensity: mild
 Number: areas of diffuse retinal thickening and focal
leaks (if any)
 Placement: 1 to 2 burn-widths apart (500-3000 μm from
center of fovea)
 Wavelength: green to yellow

18. Mechanism of Grid Laser in macular edema
 activates RPE pump to reduce edema.
 produces thinning of outer retina & reduces oxygen
consumption and increases choroidal delivery of
oxygen to the inner retina, producing a consequent
autoregulatory constriction of the retinal vasculature in
the leaking area & decreasing the edema.

19. Grid macular laser for macular edema.
(A) FA, late phase, demonstrating macular edema with
foveal involvement.
(B) Immediate post treatment fundus photograph
showing grid pattern of laser photocoagulation.

20.  BRVO
FFA informative FFA not
informative
FU x 4 months
No
NVE/ME
NVE +
ME +
NVE -
ME +
NVE +
ME -
FU X 4 M S/
G
G laser S
laser

21. Central Vein Occlusion Study
(CVOS)

22. Treatment of Macular edema
Central Vein Occlusion Study (CVOS ) Group
 Objectives –
 To undersatnd the natural history of perfused CRVO
 To determine whether macular grid laser improves V/A in eyes with macular oedema
 To determine whether early PRP prevents NVI
 To determine the timing of PRP, before or after the onset of neovascularization.
 728 eyes with CRVO
 Groups –
 Perfused (P)
 Non-perfused (N)
 Indeterminate (I)
 Macular oedema (M)
 Laser parameters –
 PRP – 500 – 1000 u, 0.2 sec duration , moderate intensity burns
 Grid – 100u, 0.1 sec duration , moderate intensity burns, within 2 DD from the centre of the
fovea.

23.  Conclusions –
 1/3rd
of perfused CRVO convert to non-perfused within 3 yrs
 Grid laser is not recommended for macular oedema, its use in patients
> 65yrs is yet to be determined
 Majority of (I) are non-perfused
 Prophylactic PRP is not recommended
 Prompt PRP at the first sign of NVI diminishes the development of NVG
 No effective treatment for ischaemic CRVO.
 PRP –
 Treatment of choice in ischaemic CRVO to prevent and cause regression of
neovascularization
CRVO Treatment Study

24. Follow - up
 Perfused –
 Every 2-3 months for 6 months, then yrly for 3 yrs
 Non-perfused –
 Every month for first 6 months, then yrly
 Macular oedema -
 Every month for first 6 months, then yrly

25. Treatment of Neovascularization
 The most serious complication of CRVO is
neovascularization.
 NVE occurs less frequently than NVI, and usually only in
ischemic occlusions.
 The low incidence of retinal surface neovascularization in
ischemic CRVO is thought to be due to the destruction of
endothelial cells, which provide the source for endothelial
proliferation and neovascularization.

26. RECOMMENDATIONS OF CVOS
 PRP be delivered promptly after the development
of NVI/NVA but not prophylactically in eyes with
nonperfused CRVO .
 Persons presenting with NVD/NVE without NVI/NVA
should be treated with PRP,

27. INTRAVITREAL STEROIDS

29. INTRAVITREAL STEROIDS
 Triamcinolone Acetonide :
 Preserved : Kenalog
 Preservative free :
 Trivaris (Allergan) : SCORE study
 Triesence (Alcon)
 Dexamethsone :
 Ozurdex (Allergan) : Ozurdex-GENEVA study

30. The Standard Care versus COrticosteroid
for REtinal Vein Occlusion Study
(The SCORE Study)

31. OBJECTIVE:
To compare the efficacy and safety of 1-mg and
4-mg doses of preservative-free intravitreal
triamcinolone (IVTA) with standard care (grid
photocoagulation) for eyes with vision loss
associated with macular edema secondary to
BRVO.
 preservative-free, sterile, single use, nondispersive formulation of triamcinolone
was used, brand name TRIVARIS; Allergan, Inc, Irvine, California ) in 1-mg and
4-mg doses. administered in a volume of 0.05 mL.

32. Gain of
>15
letters
Cataract
surgery
IOP
lowering
medicines
grid 29% 13% 2%
1 mg 28% 25% 7%
4 mg 27% 35% 41%

33. SCORE BRVO Conclusion
 Consensus : Grid laser (standard care) : the
treatment for macular edema secondary to BRVO
 Similar efficacy in all 3 groups up to month 12
 Improved efficacy for laser beyond month 12
 Superior safety profile of laser over 1-mg and 4-
mg Triamcinolone

34. SCORE CRVO
 To compare the Efficacy and Safety of Intravitreal
Triamcinolone With Observation to Treat Vision
Loss Associated With Macular Edema Secondary to
Central Retinal Vein Occlusion

35. Objective
 To compare the efficacy and safety of 1-mg and 4-
mg doses of preservative-free intravitreal
triamcinolone with observation for eyes with vision
loss associated with macular edema secondary to
perfused central retinal vein occlusion (CRVO).

36. Observation 1 mg 4 mg
>15 letter gain in
VA
6.8% 26.5% 25.6%

37. Comments
 Natural history of untreated CRVO is poor, with
only 7% showing a gain in visual acuity of >15
letters as compared to IVTA group (26%).
 Although OCT showed decrease in all the groups,
maximum visual acuity gain was found in IVTA
group.
 This could be due to anti- VEGF , antiinflammatory
and possible neuroprotective effect of coriticosteroids .

38.  Both 1 mg and 4 mg groups had comparable results
in terms of visual efficacy
 The adverse event profile is dose dependent

39. SCORE CRVO Conclusion
 Intravitreal triamcinolone effective in improving
visual acuity
 1 mg triamcinolone preferred for better safety
profile

40. Global Evaluation of
implaNtable DexamEthasone in retinal Vein
occlusion
with macular edemA
GENEVA

41. OZURDEX™
(dexamethasone intravitreal implant)
• Injectable, biodegradable intravitreal implant contains 0.7 mg (700
μg) dexamethasone in the NOVADUR™
solid polymer drug
delivery system (preservative-free).
• Poly (D,L-lactide-co-glycolide) PLGA biodegradable polymer matrix, which slowly
degrades to lactic acid and glycolic acid as dexamethasone is gradually released.

42. Ozurdex Key Adverse Events
*Intravitreal injections have been associated with endophthalmitis.
OZURDEX™
(n=421)
Sham
(n=423)
Ocular
IOP increased 106 (25%) 5 (1%)
Conjunctival hemorrhage 85 (20%) 63 (15%)
Eye pain 31 (7%) 16 (4%)
Conjunctival hyperemia 28 (7%) 20 (5%)
Ocular hypertension 17 (4%) 3 (1%)
Cataract 15 (4%) 6 (1%)
Vitreous detachment 12 (3%) 8 (2%)
Sterile or infectious
endophthalmitis* 0 0
Retinal detachment 1 (0.2%) 1 (0.2%)
Nonocular
Headache 14 (3%) 7 (2%)
Increased IOP with dexamethasone intravitreal implant (OZURDEX™) 0.7 mg peaked at day 60 and returned to
baseline levels by day 180.

43.  Anti-VEGFs
 Vitrectomy
 Chorioretinal anastomosis
 Arteriovenous sheathotomy
Newer Treatments
Anti-VEGFs are most widely used

44. INTRAVITREAL PHARMACOTHERAPY
 AVASTIN ( Bevacizumab )
 LEUCENTIS ( Ranibizumab )
CRVO : CRUISE Study
BRVO : BRAVO Study
 PEGAPTANIB SODIUM ( Macugen )
 EYLEA ( Aflibercept )
 INTRAVITREAL IMPLANT

45. Role of VEGF-A in angiogenesis
 Stimulates angiogenesis
 Increase permeability
 Chemotactic factor for
inflammatory cells –
Promotes inflammation

46. VEGF-A is present in the healthy eye
 VEGF and its receptors naturally
expressed in healthy eye
 High concentrations of VEGF
in RPE
 Receptors primarily located on
vascular endothelial cells
 In healthy eye, VEGF may play a
protective role in maintaining
adequate blood flow (choroidal)
to RPE and photoreceptors
Witmer et al, Prog Retin Eye Res, 2003; Adamis and Shima, In press; Kim et al, Invest Ophthalmol Vis Sci, 1999; Ambati et al, Surv Ophthalmol, 2003;
Zarbin, Arch Ophthalmol, 2004.
Photo used courtesy of the AREDS Research Group.
Fundus photo of normal retina

47. Pathologic
VEGF-A secreted by RPE
• Hypoxia
• Accumulation of lipid metabolic
byproducts
• Oxidative stress to retina & RPE
• Alterations in Bruch’s membrane
• Drusen (Reduction in the
choriocapillaries blood flow and block
diffusion of oxygen and nutrients to RPE
and photoreceptors)
Initiating stimuli for VEGF release
Witmer et al, Prog Retin Eye Res, 2003; Ferrara et al, Nat Med, 2003. 47

50. RanibizumaB for the Treatment of Macular
Edema following BRAnch Retinal Vein
Occlusion (BRAVO) Study

51. BRAVO Study
 Six-month phase 3 study with 6 months of follow-up
 20/40 to 20/400 (mean 20/ 80)
 CST 250 microns (mean 488 µ sham,
552 µ ranibizumab)
 Foveal center ME within 12 months
 Perfused BRVO
Campochiaro PA et al. Ophthalmology. 2010;117:1102-1112.

52. A Study of the Efficacy and Safety of Ranibizumab Injection in Patients
With Macular Edema Secondary to Branch Retinal Vein Occlusion
(BRAVO)
 397 pt.
 3 groups
o 0.3mg ranibizumab
o 0.5mg ranibizumab
o Sham
 Monthly injections for 6
months
 eligible for laser rescue T/t at 3
mths if
- Macular edema showed little
or no improvement
- VA 20/40 or worse
- CFT ≥ 250 µm
 12 months study ; 6 months
data published in June 2010

55. 6 months result

56. CONCLUSION:
Intraocular injections of 0.3 mg or 0.5 mg
ranibizumab provided rapid, effective treatment for
macular edema following BRVO.

57. Ranibizumab for Macular Edema after Central
Retinal Vein OcclUsIon Study: Evaluation of
Safety and Efficacy
CRUISE

58. Intravitreal anti- VEGF : CRUISE
Trial

59. CRUISE STUDY

61. Results at 6 months

62. Conclusions
 Monthly injections of Ranibijumab are effective in
improving VA & reducing macular edema.
 Low rates of adverse events
 This study prompted FDA approval of ranibizumab
for the treatment of CRVO .

63. VEGF Trap – Eye for RVO

64. COntrolled Phase III Evaluation of Repeated
INtravitreal Injection of VEGF Trap Eye in
CRVO: Utility and Safety Study
COPERNICUS

65. General Assessment Limiting InfiLtration of
Exudates in CRVO with VEGF Trap Eye: study
GALILEO

66. Key inclusion criteria
 1. Macular edema secondary to CRVO with CRT ≥
250 μm
 2. ETDRS BCVA of 20/40 to 20/320 in the study
eye

67. Key exclusion criteria
 1. Previous use of intraocular or periocular
corticosteroids in the study eye
 2. Previous treatment with anti-angiogenic drugs in
the study eye
 3. Prior panretinal laser photocoagulation or
macular laser photocoagulation in the study eye
 4. CRVO disease duration > 9 months

68. Treatment groups and
randomization
 Patients were randomized 3:2 to 2-mg VEGF Trap-
Eye or sham injections every 4 weeks upto week 24.
 Week 24 to Week 52, patients received either 2-
mg VEGF Trap-Eye as needed (p.r.n.) or sham
injections based on re-treatment criteria.

69. Outcomes
 Primary endpoint: The proportion of patients who
gained ≥ 15 ETDRS letters from baseline at Week
24
 Key secondary endpoint: The change in BCVA from
baseline to Week 24

71. After week 24
RESULTS

72. Efficacy
 Statistically significant differences between patients
receiving VEGF Trap-Eye compared with sham were
seen at Week 24 in both studies

73.  Proportion of Patients Who Gained ≥15 ETDRS
Letters From Baseline
2 mg VEGF Trap
Eye
Sham P value
COPERNICUS 56.1% 12.3% <0.0001
COPERNICUS 60.2% 22.1% <0.0001

74.  Mean Change From Baseline for BCVA in ETDRS
Letters
2 mg VEGF Trap
Eye
Sham P value
COPERNICUS 17.3 -4 <0.001
COPERNICUS 18.0 3.3 <0.0001

75. Safety
 2-mg VEGF Trap-Eye treatment was generally well
tolerated
 COPERNICUS: The most frequently reported
treatment-emergent adverse events (TEAEs) were
conjunctival hemorrhage, visual acuity reduced, and
eye pain
 GALILEO: eye pain, conjunctival hemorrhage, and
elevated IOP

76. BRVO Summary
 BRVO:
 SCORE: Laser better than IVTA
 OZURDEX: Dexamethasone better than sham (no laser
arm)
 BRAVO: Ranibizumab monthly for 6 months better than
observation in BRAVO. Improved VA: 61% vs 29% eyes
gained 15 or more letters

77. BRVO Summary
 BRVO:
 SCORE: Laser better than IVTA
 OZURDEX: Dexamethasone better than sham (no laser
arm)
 BRAVO: Ranibizumab monthly for 6 months better than
observation in BRAVO. Improved VA: 61% vs 29% eyes
gained 15 or more letters
 VEGF TRAP appears beneficial in initial studies

78. CRVO Summary
 CRVO treatment options
 Steroids beneficial in phase 3 studies
 SCORE Study: IVTA vs observation
 OZURDEX Trials: dexamethasone vs sham
 Anti-VEGFs
 CRUISE: Ranibizumab monthly for 6 months better than
observation. Improved VA: 48% vs 17% eyes gained 15 or
more letters
 VEGF TRAP appears beneficial in initial studies

79. for Ischemic Central Retinal Vein Occlusion
Rubeosis Anti-VEGF (RAVE)
Trial

80.  utilizes monthly intravitreal Ranibizumab injections
for 9 months to see if total VEGF blockade will
prevent neovascular glaucoma and eliminate the
need for panretinal photocoagulation in patients
with ischemic central retinal vein occlusion.

81. When to start treatment ????
 no timely treatment photoreceptor
damage/cell death/ permanent cystoid changes
 irreversible VA loss

82. Role of peripheral ischemia
 Using Wide-field FFA
 Eyes with more edema, often have more peripheral
ischemia
 Anti – VEGFs decrease both

83. RELATE STUDY
 Ranibizumab DosE Comparison and the Role of
LAser in the managemenT of REtinal Vein
Occlusions (RELATE)
 Ongoing study
 If higher doses of anti-VEGF more effective
 If Laser treatment of peripheral ischemia could
decrease the no. of injections

84. Role of LASER in RVO begins to
evolve
 Ultra wide field FFA view of periphery
 If ischemia do PRP
 PRP decreases VEGF production / inflammation
 Decreased ME

85.  If targeting PRP to only peripheral ischemic areas
can stop the cycle of ischemia while preserving
more peripheral vision ???

86. Limitations
 Various studies are incomparable
 Unmatched in design
 Wide disparity in the sham groups
 Apart from ME, other facets like ocular
neovascularisation , scantily studied

87.  No robust evidence as to how the concurrent
systemic abnormalities , affect the course and
consequences of RVO, with or without intervention.

88.  VEGFs are only small link in cascade involved in
pathogenesis of RVO
 Maintaining a normal balance b/w anti angiogenic
and proangiogenic factors would be more suitable
approach rather than targeting only proangiogenic
VEGFs

89. Thank you