RVO risk factors and management pearls

RVO: Risk Factors and Management Pearls
Yasuo Yanagi
A/Prof Duke NUS Medical School
Singapore National Eye Centre
Singapore Eye Research Institute

1. Shahid et al. Br J Ophthalmol 2006; 90: 627-639; 2. Mitchell et al. Arch Ophthalmol 1996; 114: 1243-1247;
3. Rogers et al. Ophthalmology 2010; 117: 313-319; 4. Arakawa et al. Invest Ophthalmol Vis Sci. 2011; 52:
Prevalence of RVO2
agePrevalence(%)
0
1
2
3
4
5
<60 60-69 70-79 >80
Retinal vein occlusion (RVO)
• Among the most common retinal diseases1
• 16.4M adults3
– 2.5M CRVO
– 13.9M BRVO
• 520/1M persons per year3
• Occurs most commonly in 7th decade4
Age-and sex standardized prevalence2
• 0.44% ：BRVO
• 0.08% ：CRVO

Classification of RVO
Major BRVO
(first-order branch occlusion)
- Usually involve retinal veins near the optic disc
Minor BRVO
(second-order branch occlusion)
- Usually involve one of the macular venules
Diagnosis

Old BRVO
Serous retinal detachment
Retinal edema
Lipid exudate
Diagnosis

Old BRVO
Early frame Late frame
Occluded vein
Tortuous collateral vessels crossing the horizontal raphe
Diagnosis

Classification of CRVO
Non-ischemic CRVO
(perfused CRVO)
Ischemic CRVO
(non-perfused)
Ischemic index of 50% (corresponding to about 10
disc diameters of retinal capillary non-perfusion) on
FA 1
1. Central Vein Occlusion Study Group. Arch Ophthalmol 1993; 111: 1087-1095.
Diagnosis

CRVO with cilioretinal artery occlusion Diagnosis

Old CRVO 59y.o. M
Diagnosis
Retinochoroidal collaterals,
a.k.a., optociliary shunts
or opticociliary anastomoses

Pathogenesis of RVO
Narrowed vein
Venous outflow↓
Increased vein pressure
VEGF↑↑
Ischemia
bleedingedema
Neovascular
complications
Endothelial damage Capillary occlusion
Flow turbulence
Blood flow↓
BRVO CRVO
Atherosclerosis,
Optic nerve swelling
*: Starling’s law
*
Arteriovenous (AV)
crossing sites
Pathogenesis
VEGF↑, inflammation
(IL-6, IL-8, MCP-1 etc)
Partial thrombosis

Pathogenesis of RVO
NVI
CME
NVE
NVD
22% in BRVO
Pathogenesis
in about 50% of eyes with ischemic CRVO

Risk factors and associated diseases in RVO
1.Shahid et al. Br J Ophthalmol 2006; 90: 627-639; 2. Mitchell et al. Arch Ophthalmol 1996; 114: 1243-1247; 3. Rath et al. Ophthalmology 1992; 99:
502-514; 4. Hayreh et al. Am J Ophthalmol 2001; 131: 61-77; 5. Elman et al. Ophthalmology 1990; 97: 1543-1548; 6. Wong et al. Ophthalmology 2005;
112: 540-547; 7. Cheung et al. Invest Ophthalmol Vis Sci 2008; 42: 4297-4302
Glaucoma
High IOP2
Risk factors for
BRVO
Hypertension3-6
age1
Diabetes4-6
Hyperlipidemia5
Cardiovascular
deiseases1
Smoking2
Kidney diseases7
Additional risk
factors for
CRVO
Plasma viscosity1
Systemic risk factors Local risk factors

Symptoms
• CRVO: Blurred vision in the involved eye after getting up
• BRVO: Visual acuity may be unaffected to severely impaired depending on the localization of BRVO
1. Shirodkhar et al. Br J Hosp Med 2012; 73: 20-23; 2. Central Vein Occlusion Study Group. Arch Ophthalmol 1993; 111: 1087-1095;
3. McIntosh. Ophthalmology 2010; 117: 1113-1123 1）The Royal College of Ophthalmologists: Interim guidelines for management of retinal vein occlusion.
London: The Royal College of Ophthalmologists; 2010. 2）Wong T.Y., et al.: N Engl J Med. 363（22）, 2135（2010）. 3） The Central Vein Occlusion Study Group :
Arch Ophthalmol. 115(4), 486（1997）
Macula edema is the most common cause of visual loss due to RVO1
BRVO: at the end of 3yr CRVO: at the end of 3yr
n=304
>6/60
63％
< 6/12 40％
Baseline VA
6/6 to 6/60
<6/60
37％
n=201
>6/60
20％
Baseline VA
< 6/60
<6/60
80％
治療3年後の視力
>6/12
60％
6/60 to 6/12
28％
<6/60
12％
n=139

Treatments of RVO1,2
1.Lattanzio R, et al. Ophthalmologica 2011;225:135-43; 2.Ozurdex (dexamethasone intravitreal implant) 0.7 mg
• Anti-VEGF therapy
• Scatter photocoagulation
• Macular grid
photocoagulation
• Dexamethasone implant
• IVTA*
• Surgery
• Anti-VGEF therapy
• PRP
• Dexamethasone implant
• IVTA*
• Surgery
CRVOBRVO
Treatment
Goal of therapy should be to
prevent neovascular complications and chronic macular edema

Treatment to prevent neovascular complications
Shahid et al. Br J Ophthalmol 2006; 90: 627-639
Management BRVO CRVO

x

x





x
x


Neovascularization secondary to RVO
Scatter or pan- retinal photocoagulation
Anticoagulant therapy
Thrombolysis (intravitreal, retinal vein, ophthalmic artery)
Hemodilution
Radial optic neurotomy
Cilioretinal anastomosis formation
Cannulation with tissue-type plasminogen activator
Arteriovenous sheathotomy
Treatment

Treatment of neovascular related complications
CRVO
• PRP - after iris/angle
neovascularization has
developed.
• Careful observation of
eyes with CRVO not to
overlook
neovascularization.
BRVO
• Scatter photocoagulation
- Only when preretinal
neovascularization is
present.
• Patients with areas of
capillary nonperfusion
>5DA - closely followed
for the development of
neovascularization.
If close follow-up is not possible, early PRP may
be considered in high risk patients.
Treatment

Retinal photocoagulation
Treatment

Surgery for RVO?- no evidence-based results
Chorioretinal anastomosis4,5
Therapeutic goal of the surgery is to either decompress or cannulate the
affected vein and to solve the obstructive process in the vascular lumen 1
Vitrectomy3
Radial Optic Neurotomy6
Vessel cannulation1,2
1.Lattanzio R, et al. Ophthalmologica 2011;225:135-43; 2.Hattenbach L, et al. Invest Ophthalmol Vis Sci 2012;53:42-6;
3.Baharivand N, et al. Clin Ophthalmol 2011;5:1089-93; 4.Wong TY, Scott IU. N Engl J Med 2010;363:2135-44;
5.Mirshahi A, et al. Br J Ophthalmol 2005;89:64-9; 6.Ramezani A. J Ophthalmic Vis Res 2009;4:115-21
Treatment

BRVO CRVO
Grid-pattern
photocoagulation
VA<6/12, without capillary perfusion1 Not recommended. No benefit of grid
laser treatment in CRVO in terms of
VA2
Intravitreal triamcinolone
acetate (IVTA)
SCORE Studies3
Dexamethasone implant
(Ozurdex)
Geneva study4
Anti-VEGF treatment Currently 2 anti-VEGF agents (ranimizumab and aflibercept) have been FDA
and EMA approved for the treatment of RVO, while another VEGF inhibitor
(bevacizumab) is often used "off-label" in clinical practice.5,6
Treatment for macular edema
1. Branch Vein Occlusion Study Group. Arch Ophthalmol 1986; 104: 34-41; 2. Central Vein Occlusion Study Group. Ophthalmology 1995; 102: 1434-1444; 3. Scott et al. Arch
Ophthalmol 2009; 127: 1115-1128; 4. Haller et al. Ophthalmology 2010; 117: 1134-1146;
5. Campochiaro et al. Ophthalmology 2010; 117: 1102-1112; 6. Brown et al. Ophthalmology 2010; 117: 1124-1133
Treatment
• Standard treatment for many years for ME was
grid-pattern photocoagulation in BRVO and observation in CRVO.

Grid-pattern photocoagulation
Vertical scan
0:37
9:29
Treatment

Treatment

Vertical scan
Treatment

IVTA: SCORE-BRVO
0%
5%
10%
15%
20%
25%
30%
Standard Care 1mg 4mg
Increaseof>15lettersfrombaselineto12m(%)
Standard care = Grid-pattern photocoagulation
IVTA: every 4 months
Scott et al., Arch Ophthalmol 2009: 127; 1115-28
(n=137) (n=136) (n=138)
Treatment
IVTA is as effective as macular grid photocoagulation in BRVO

IVTA: SCORE-CRVO
0%
5%
10%
15%
20%
25%
30%
Sham 1mg 4mg
Increaseof>15lettersfrombaselineto12m(%)
IVTA: every 4 months
Iq et al., Arch Ophthalmol 2009: 127; 1101-14
P<0.0001
P<0.0001
(n=88) (n=92) (n=91)
Treatment
Mean visual gain was -1.2 letters in both the 1 and 4 mg groups compared with -7 letters in the observation group.
IVTA is superior to observation in CRVO

Steroids – other studies
GENEVA trial - the combined results at 6 months –
15-letter improvement; 41% and 40% of patients using the 0.7 and 0.35 mg
dexamethazone (DEX) groups, respectively, compared with 23% in the sham group.
A post hoc analysis of SCORE-CRVO and GENEVA –
Patients with more recent onset edema responded better than patients with more chronic edema.
The COMORADE-B and C study*
- head to head, ranibizumab PRN vs DEX –
Superior efficacy of ranibizumab compared to DEX in patients with BRVO and CRVO.
- Steroids would not be the preferred first line choice
*:Hoerauf et al., AJO 2016

BRVO CRVO
Grid-pattern
photocoagulation
VA<6/12, without capillary perfusion1 Not recommended. No benefit of grid
laser treatment in CRVO in terms of
VA2
Intravitreal triamcinolone
acetate (IVTA)
IVTA is as effective as macular grid photocoagulation, but steroid-related
adverse effects such as cataract and glaucoma are not rare3
Dexamethasone implant
(Ozurdex)
Slightly better functional outcome for CRVO patients. Increased intraocular
pressure and cataract progression was frequent.4
Anti-VEGF treatment Currently 2 anti-VEGF agents (ranimizumab and aflibercept) have been FDA
and EMA approved for the treatment of RVO, while another VEGF inhibitor
(bevacizumab) is often used "off-label" in clinical practice.5,6
Treatment for macular edema
1. Branch Vein Occlusion Study Group. Arch Ophthalmol 1986; 104: 34-41; 2. Central Vein Occlusion Study Group. Ophthalmology 1995; 102: 1434-1444; 3. Scott et al. Arch
Ophthalmol 2009; 127: 1115-1128; 4. Haller et al. Ophthalmology 2010; 117: 1134-1146;
5. Campochiaro et al. Ophthalmology 2010; 117: 1102-1112; 6. Brown et al. Ophthalmology 2010; 117: 1124-1133
Treatment
• Standard treatment for many years for ME was
grid-pattern photocoagulation in BRVO and observation in CRVO.

Pivotal studies of anti-VEGF drugs for BRVO and CRVO
CRVOBRVO
BRAVO (n=397)
HORIZON-BRAVO (n=205)
RETAIN-BRAVO (n =34)
SHORE
BRVO (n=115), CRVO (n=87)
VIBRANT (n=183)
BRIGHTER (n=445)
MARVEL (n=75)
CRUISE (n=392)
HORIZON-BRAVO (n=304)
RETAIN-BRAVO (n =32)
COPERNICUS (n=189)
CRYSTAL (n=357)
Lucentis
Eylea
Lucentis
Eylea
Lucentis vs Avastin
Lucentis PRN vs Monthly
RELATE
BRVO (n=40), CRVO (n=40)
Lucentis 0.5 mg vs 2.0mg

HORIZON RVO1,2 : study design
4. Brown et al. Ophthalmology 2011; 118: 1594
5. Brown et al. Ophthalmology 2010; 117: 1124
6. Campochiaro et al. Ophthalmology 2011; 118: 2041
† months 6-11：Lucentis PRN
* Follow-ups were set every 3 months and patients were injected if CFT was <250 μm or there were signs of vision-threatening edema.
1. http://www.clinicaltrials.gov/ct2/show/NCT01442064
2. Heier et al. Ophthalmology 2012; 119: 802-93
3. Campochiaro et al. Ophthalmology 2010; 117: 1102
Study completion: Month 24
Lucentis 0.5mg PRN* every 3 months
HORIZON（Cohort2 ［n=608］）
Lucentis0.5mg
Primary endpoint (month6)
Secondary endpoint (month12; n=356)
CRUISE5,6 （CRVO）［N=392］
Primary endpoint (month6)
Secondary endpoint (month12; n=356)
Sham/
Lucentis
0.5mg†
Lucentis
0.5mg†
Lucentis
0.3mg†
Sham/
Lucentis
0.5mg†
Lucentis
0.5mg†
Lucentis
0.3mg†
BRAVO3,4 （BRVO）［N=397］
Treatment

Horizon mean change in visual acuity from baseline
1）Heier et al. Ophthalmology 2012;119:802-
Sham group switched to
Lucentis 0.5mg PRN＊
-5
25
120 63 9
10
20
15
5
+12.0
+7.6
Monthly PRN
CRUISE
+16.2
+9.4
HORIZON RVO
0
Lucentis 0.5mg
Sham group＊
MeanBCVAchangefrombaseline
（letters）
Sham group switched to
Lucentis 0.5mg PRN＊
0
25
12
Lucentis 0.5mg
Sham group＊
0 63 9
10
20
15
5
+17.5
+15.6
BRAVO
+19.2
+13.2
HORIZON RVO
MeanBCVAchangefrombaseline
（letters）

Eylea
• VIBRANT and COPERNICUS studies demonstrated the
safety and efficacy ot Eylea for the treatment of
macular edema due to BRVO and CRVO, respectively.
• In COPERNICUS, both non-ischemic and ischemic
groups experienced similar gains in visual acuity and
anatomical resolution of macular edema.
• Eylea is at least equally as effective as Lucentis, but
there is insufficient data to conclude that Eylea is
better than Lucentis.
Mean # of injections Change in BCVA ≥15 letters gain
VIBRANT
(Eylea)
Aflibercept Aflibercept Grid-pattern laser Aflibercept Grid-pattern laser
8.7 17.1 12.2 57% 41%
BRAVO
(Ranibizumab)
0.3 mg 0.5 mg 0.3 mg 0.5 mg Sham 0.3 mg 0.5 mg Sham
8.3 8.4 16.4 18.3 12.1 56% 60% 44%
BRVO
Mean # of injections Change in BCVA ≥15 letters gain
COPERNICUS
(Eylea)
Aflibercept Aflibercept Sham Aflibercept Sham
8.5 16.2 3.8 55% 30%
CRUISE
(Ranibizumab)
0.3mg 0.5mg 0.3mg 0.5mg Sham 0.3mg 0.5mg Sham
9.6 8.8 13.9 13.9 7.3 47% 51% 33%
CRVO

Eylea
• VIBRANT and COPERNICUS studies demonstrated the
safety and efficacy ot Eylea for the treatment of
macular edema due to BRVO and CRVO, respectively.
• In COPERNICUS, both non-ischemic and ischemic
groups experienced similar gains in visual acuity and
anatomical resolution of macular edema.
• Eylea is at least equally as effective as Lucentis, but
there is insufficient data to conclude that Eylea is
better than Lucentis.

baseline
1Mo
2Mo
3Mo
4Mo
5Mo
6Mo
7Mo
8Mo
10Mo
11Mo
12Mo
14Mo
15Mo
16Mo
18Mo
baseline
18Mo
Vd=6/20
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/7.5
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/6
Vd=6/7.5
Vd=6/6
Vd=6/6
Vd=6/6
Avastin (off-label)
BRVO, 60y.o. F
+IVB
+IVB
+IVB +IVB
+IVB
+IVB
Treatment
High-dose?
Monthly vs PRN?

Posology of Anti-VEGF drugs
• High dose?
The RELATE study - there was no significant difference
between 0.5-mg and 2.0-mg ranibuzumab groups with regards
to visual outcome.
(Although the 2.0-mg dose showed significant improvement with regards to
central foveal thickness for CRVO, not BRVO.)
• h the PRN and monthly dosing regimens achieved similar
results.
• Laser failed to increase edema resolution or to reduce the
ranibizumab injections between weeks 24 and 144.
Change in BCVA
Change in BCVA
From week 24 to 144
0.5 mg 2.0 mg Ranibizumab
Ranibizumab +
laser
RELATE -
BRVO
12.1 14.6 -6.7 +0.4
RELATE-
CRVO
15.5 15.8 +3.1 -2.6
every 4 weeks to 24 weeks
-> second randomization to ranibuzumab vs ranibizumab + laser

Posology of Anti-VEGF drugs
Monthly vs PRN dosing regimen?
The SHORE study - after achieving visual and OCT stability
criteria, both the PRN and monthly dosing regimens achieved
similar results.
Mean # injections Change in BCVA
% of eyes gaining 15 letters
(both CRVO and BRVO)
SHORE-
BRVO
Monthly PRN Monthly PRN
Monthly PRN
7.6 3.8 18.7 21
SHORE-
CRVO
Monthly PRN Monthly PRN
66% 70%
7.6 3.6 18.8 18
PRN – months 7 - 15

New evidence – BRVO: BRIGHTER study
Study design: 24-month, prospective, open-label, randomized, active-controlled,
multicenter, phase 3b study
Randomization: 2:2:1 to receive ranibizumab (n=183), ranibizumab with laser
(n=180), or laser only (n=92).
Treatment: Patients treated with ranibizumab received a minimum of three initial
monthly ranibizumab injections until VA stabilization and VA-based PRN dosing
thereafter. Laser was performed at the investigator’s discretion at a minimum
interval of four months and if VA was <79 letters.
Tadayoni R et al; BRIGHTER study group. Ophthalmology. 2016;123:1332-1344.
Study objectives
To establish the efficacy of a stability-driven individualized PRN treatment
regimen in patients with visual impairment due to macular edema
secondary to BRVO.

New evidence – BRVO: BRIGHTER study
Results
1. Ranibizumab with or without laser was superior to laser only in improving mean
BCVA from baseline at month 6 (P< 0.0001).
2. Patients with a shorter BRVO duration at baseline had a higher mean BCVA gain
than those with a longer BRVO duration.
3. Patients with a poor baseline VA had a better BCVA gain than those with a higher
baseline VA, although final BCVA was lower in those with poor baseline VA.
4. The presence of macular ischemia at baseline did not influence mean BCVA
gains.
Tadayoni R et al; BRIGHTER study group. Ophthalmology. 2016;123:1332-1344.
Change in BCVA % of eyes gaining 15 letters
Ranibizumab
Ranibizumab
+ laser
Laser Ranibizumab
Ranibizumab
+ laser
Laser
14.8 14.8 6.0 45% 47% 28%

New evidence – CRVO: CRYSTAL study
Study design
24-month, prospective, open-label, single-arm, multicenter study to assess
the efficacy and safety profile of an individualized regimen of ranibizumab
driven by stabilization criteria in patients with macular edema secondary to
CRVO (n=357).
Treatment
Patients received a minimum of three initial monthly ranibizumab injections
until VA stabilization and VA-based PRN dosing thereafter if monthly
monitoring indicated a loss of VA resulting from disease activity.
Larsen M et al; CRYSTAL Study Group. Ophthalmology. 2016;123:1101-1111.
Study objectives
To establish the efficacy of a stability-driven individualized PRN treatment
regimen in patients with visual impairment due to macular edema
secondary to CRVO.

New evidence – CRVO: CRYSTAL study
Results
1. Ranibizumab treatment resulted in a statistically significant mean gain in
BCVA from baseline at month 12 of 12.3 letters. The mean number of
ranibizumab injections up to month 12 was 8.1.
2. At month 12, mean BCVA gains were similar with or without macular
ischemia at baseline (11.6 vs 12.1 letters)
3. the mean BCVA gain was higher with baseline CRVO duration of less than
three months (13.4 letters) than with a longer duration (≥3 to <9 months,
11.1 letters; ≥9 months, 10.9 letters).
4. Patients with lower baseline BCVA had larger mean BCVA gains at month 12
than those with higher baseline BCVA, although the absolute BCVA at month
12 was higher with higher baseline BCVA.
Larsen M et al; CRYSTAL Study Group. Ophthalmology. 2016;123:1101-1111.
STUDY
Mean # of
injections
Change in BCVA % of eyes gaining 15 letters
Crystal 8.1 12.3 49%
Cruise
(0.5mg group)
9.6 13.9 51%

Take home message
Anti-VEGF agent: as first-line therapy for BRVO- and CRVO- associated macular
edema.
Grid-pattern laser: only in BRVO, if the patient refuses anti-VEGF therapy
Steroids: generally reserved for refractory cases or if the patient refuses anti-
VEGF therapy.
Treatment should be initiated as soon as the diagnosis is established.
All three anti VEGF drugs has similar effect in terms of VA gain.
PRN (based on VA stablisation) is recommended for individualized treatment.
Long term monitoring is necessary to maintain the reduction in edema and
improvement in vision. Endeavors to optimize therapeutic outcomes in patients
with RVO while decreasing treatment burden are desirable.
Anti-VEGF therapy revolutionized the management of RVO.

RVO risk factors and management pearls

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