BRVO.ppt

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August 2016 UKEYL08160072
Branch Retinal Vein Occlusion
Current understanding and
approaches to treatment
Prescribing information can be found on the last two slides

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About this slide deck
• This slide deck is provided as a service to medicine by Bayer and is
intended for educational use with healthcare professionals only
• Prescribing information for EYLEA (aflibercept solution for
injection) is at the end of the slide deck, and is also available
in accompanying material.
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Tel: 01635 563500; E-mail: pvuk@bayer.com

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Acknowledgements
The contribution of the following in the development of this resource is gratefully acknowledged:
• Peter Addison, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust
• Sanjiv Bannerjee, Consultant Ophthalmologist, University Hospital Wales
• Michael Briggs, Consultant Ophthalmologist, Spire Liverpool Hospital
• Ben Burton, Consultant Ophthalmologist, James Paget University Hospital
• Louise Downey, Consultant Ophthalmologist, Hull Royal Infirmary
• Samer Elsherbiny, Consultant Ophthalmologist, Birmingham and Midland Eye Centre
• Richard Gale, Consultant Ophthalmologist, York Teaching Hospital
• Praveen Patel, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust
• Adam Ross, Consultant Ophthalmologist, Bristol Eye Hospital
• Gavin Walters, Consultant Ophthalmologist, Harrogate District Hospital and York Hospital
• Yit Yang, Consultant Ophthalmologist, Wolverhampton Eye Hospital and Visiting Professor,
Aston University

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Discussion topics
BRVO = branch retinal vein occlusion.
• Definition of retinal vein occlusion
• Epidemiology of RVO
• Vision loss in BRVO
• Pathophysiology
• Natural history
• Clinical signs and imaging features
• Initial management
• Management of macular oedema
• Management of other complications

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Background and epidemiology
of BRVO

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• The type of RVO depends on the location of the occlusion1
• In the literature, HRVO is defined as an RVO that involves two
retinal quandrants2,3
HRVO
Occlusion of the
superior/inferior
branch of the central
retinal vein
RVO is an obstruction of one of the veins
that drains blood away from the retina
BRVO = branch retinal vein occlusion; CRV = central retinal vein; CRVO = central retinal vein occlusion;
HRVO = hemiretinal vein occlusion; RVO = retinal vein occlusion.
1. Kiire CA, Chong NV. BMJ. 2012;344:e499; 2. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1;
3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544;
BRVO
Occlusion of a
branch retinal vein
CRVO
Occlusion of the central
retinal vein

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Common sites of retinal vein occlusion1
Image courtesy of Yit Yang.
BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion.
1. Kiire CA, Chong NV. BMJ. 2012;344:e499.
Blue arrow
Point at which the
central retinal vein
exits the eye – a
common site for
CRVO
Yellow arrow
An arteriovenous
crossing – a typical site
for BRVO

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RVO is a major cause of vision loss
RVO = retinal vein occlusion.
1. Laouri M, et al. Eye. 2011;25:981–988; 2. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines,
July 2015; 3. UK Government Driving Eyesight Rules. Available here: https://www.gov.uk/driving-eyesight-rules. Accessed March 2016.
• RVO is the second most common sight-threatening
retinal vascular disorder (after diabetic retinopathy)1
– RVO is unilateral in most patients2
– Can be severe2
 Possible loss of vision to below driving standards3
 As a result, most patients are willing to undergo
invasive treatments1
• Sign of possible underlying systemic pathology2

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RVO puts a major burden on the patient’s life1
1. Sivaprasad S, Oyetunde S. Clin Ophthalmol. 2016;10:939–946.
4.5 hours
average appointment time
53% of patients
need to take ≥1 day off work
per appointment
71% of patients
require a carer’s assistance for
appointments
86%
require monthly
appointments
73%
of these require
long-term monthly
appointments

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Incidence of BRVO is greater than CRVO
1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518; 2. Cugati S, et al. Arch Ophthalmol. 2006;124:726–732.
• Beaver Dam Study (n = 4068):1
– 15-year incidence of BRVO was 1.8% versus 0.5% for CRVO
– Incidence similar in men and women (1.5% versus 2.1%)
• Blue Mountains Eye Study (n = 3654):2
– 10-year incidence of BRVO was 1.2% versus 0.4% for CRVO
– Incidence similar in men and women (2.0% versus 1.3%)
• There are no specific UK incidence data

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Incidence of RVO varies with age
1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518.
15-year cumulative incidence of BRVO and CRVO
Incidence,
%
BRVO
CRVO
Age, years

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Symptoms of BRVO
1. American Academy of Ophthalmology. Branch Retinal Vein Occlusion Symptoms. Available here:
http://www.aao.org/eye-health/diseases/branch-retinal-vein-occlusion-symptoms. Accessed March 2016.
• The main symptom of BRVO
is blurring of central vision
• Can be sudden or gradual
• Normally painless
Fundus photograph of BRVO
prior to treatment

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Causes of vision loss in BRVO:
Macular oedema1
Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion; OCT = optical coherence tomography.
1. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299.
OCT showing inferior temporal BRVO with secondary cystoid macular oedema

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Intraretinal haemorrhage1
Image courtesy of Louise Downey.
FFA mid phase showing
supero-temporal BRVO with
significant ischaemia and
masking due to retinal
haemorrhage (blue area).
Arrow indicates likely point
of occlusion

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Ischaemia and neovascularisation1,2
Image courtesy of Ben Burton.
BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography.
1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013;
FFA of superior ischaemic
(blue arrow) BRVO with
neovascularisation (yellow arrow)

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BRVO can be ischaemic or non-ischaemic
Images courtesy of Peter Addison and Ben Burton.
• Ischaemia can be macular or peripheral
Fluorescein angiography showing BRVO with
peripheral ischaemia
Colour fundus photograph and fluorescein
angiography showing BRVO with macular ischaemia

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Peripheral ischaemia can be defined
in disc diameters or disc areas
BRVO = branch retinal vein occlusion;
1. Hayreh SS, et al. Ophthalmology. 1983;90:488–506; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol.
1986;104:34–41; 3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544.
• No consensus on prevalence of BRVO with peripheral
ischaemia because of varying definitions, measurement
techniques, and patient samples1
Study Definition used
BVOS2 >5 disc diameters of non-perfusion
VIBRANT3 ≥10 disc areas of non-perfusion

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Background and epidemiology: Summary
• BRVO is an occlusion of a branch retinal vein
• Main vision-threatening complications are macular oedema,
retinal ischaemia, and neovascularisation and its sequelae
• Impact on vision depends on the location of the occlusion
• BRVO can be classified as ischaemic or non-ischaemic
• Incidence of BRVO is 1.2–1.8%
– Patients are predominantly over the age of 55 years, but BRVO
also affects the working-age population
– There are no specific data for the UK

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Pathophysiology of BRVO

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Key risk factors for BRVO1
1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015.
• Hypertension
• Diabetes
• Hyperlipidaemia
• Hyperhomocysteinaemia
• Blood coagulation disorders
• Systemic inflammatory disorders

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BRVO is considered to be the result of compression
of a vein at an arteriovenous crossing
1. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 2. Zhao J, et al. Ophthalmology. 1993;100:423–428;
3. Klein R, et al. Arch Ophthalmol. 2008;126:513–518.
• The following features of
arteriovenous crossings
contribute to the risk of
venous occlusion:
– Artery and vein share a
common adventitial sheath1
– The artery lies anterior to
the affected vein in 99%
of eyes with BRVO2
• More than half of BRVO cases
occur in the superotemporal
quadrant3
Compression
Arteriole
Bulge
Venule
Narrowing
A
V

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Thrombus formation also plays a role in the
pathogenesis of BRVO
1. Browning DJ. Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer
Science+Business Media; 2012.

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Hypothesised pathogenesis of BRVO1–3
AV = arteriovenous; BRVO = branch retinal vein occlusion; IL = interleukin; MCP = monocyte
chemotactic protein; PDGF = platelet-derived growth factor; PlGF = placental growth factor;
sICAM-1 = soluble intercellular adhesion molecule; VEGF = vascular endothelial growth factor.
1. Karia N. Clin Ophthalmol. 2010;4:809–816; 2. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 3. Browning DJ.
Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer Science+Business Media; 2012;
4. Noma H, et al. Invest Ophthalmol Vis Sci. 2014;55:3878–3885.
RVO
Stasis
Macular
oedema
Ischaemia/
hypoxia
Neovascularisation
 Pressure
Intraretinal
haemorrhage
Vitreous haemorrhage

Permeability
Compression at
an AV crossing
Degenerative changes
of vessel wall
Abnormal
haematological factors
 cytokine
production4
VEGF
PlGF
PDGF
sICAM-1
MCP-1
IL-6, 8, 12, 13

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Pathophysiology: Summary
BRVO = branch retinal vein occlusion; VEGF = vascular endothelial growth factor.
• BRVO is considered to be the result of mechanical narrowing of a
branch retinal vein lumen at an arteriovenous crossing
• Thrombus formation, as a result of Virchow’s triad, causes venous
occlusion
– Resulting occlusion leads to increased intraluminal pressure,
retinal ischaemia, upregulation of inflammatory cytokines
(including VEGF), vascular permeability and angiogenesis
• The resulting haemorrhage, neovascularisation, and macular
oedema may all lead to vision loss, the main symptom in BRVO

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Natural history and clinical signs
of BRVO

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BVOS provides information about the natural
history of BRVO
BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VA = visual acuity.
1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group.
Arch Ophthalmol. 1986;104:34–41.
• BVOS set out to answer three questions on the
effectiveness of laser photocoagulation in BRVO1,2
1
2
3

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Natural history of BRVO from BVOS
*p<0.0001 versus with treatment.
1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015; 2. Branch Vein Occlusion Study Group.
Arch Ophthalmol. 1986;104:34–41; 3. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282.
Complications2
61% of patients with neovascularisation
develop vitreous haemorrhage without
treatment
Without treatment With laser treatment
% patients with VA ≥20/40 at 3 years 34% 60%
% patients with VA ≤20/200 at 3 years 23% 12%
Average VA at 3 years 20/70* 20/40–20/50
Visual outcome3
Fellow eye involvement1
22% of patients develop
neovascularisation without
treatment
10% of patients have fellow eye
involvement over time
94–95% of patients present
with unilateral BRVO

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Clinical appearance of BRVO with
fundus photography
Image courtesy of Peter Addison.
Colour fundus photograph of long-standing BRVO

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Clinical appearance of BRVO with OCT
Image courtesy of Louise Downey.
BRVO = branch retinal vein occlusion; OCT = optical coherence tomography.
OCT of infero-temporal BRVO with secondary cystoid macular oedema

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Clinical appearance of BRVO with FA
Images courtesy of Peter Addison.
BRVO = branch retinal vein occlusion; FA = fluorescein angiography.
Early frame FA of long-standing BRVO Late frame FA of long-standing BRVO

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Signs of early-stage BRVO:
Intraretinal haemorrhage
Image courtesy of Sanjiv Banerjee.
1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013:1029–1338;
2. Optometry Today. Management & Investigation of Vascular Conditions. Module 13 Part 6: Clinical optometry.
• Intraretinal haemorrhages are
generally characteristic of
early-stage BRVO1
– Wedge-shaped distribution,
with haemorrhage apex at
occlusion site1,2
– Confined to one retinal
quadrant; distribution
determined by occlusion site1
Colour fundus photograph showing
intraretinal haemorrhage (blue area)
and cotton wool spots (yellow arrows)

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Blot haemorrhage
Colour fundus
photograph of BRVO
with blot haemorrhage
(blue area)

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Dilated, tortuous veins
Image courtesy of Robin Hamilton.
1. Browning DJ. In: Retinal Vein Occlusions. New York: Springer; 2012.
• Main clinical sign of BRVO
• Vein appears dilated before (upstream of) the occlusion,
and threadlike after (downstream of) the occlusion1
Colour fundus showing a dilated tortuous vein
(blue arrow) downstream from the occlusion
(yellow arrow)

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Collateral blood vessels form
in long-standing BRVO1
BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography; VEGF = vascular endothelial growth factor.
1. Henkind P. Aust J Ophthalmol. 1981;9:273–277; 2. Montero-Moreno JA, et al. Austin J Clin Ophthalmol. 2014;1(6):4.
• Compensatory blood vessels open up
in long-standing BRVO1
– Bypass the occlusion, diverting blood
to a non-occluded vessel
– Seen as a positive development
• Differ from vessels formed as a result
of neovascularisation:1
– Originate from capillaries and join
obstructed and non-obstructed vessels
– Do not usually leak on FA
• Development appears to be independent
of VEGF,2 hence anti-VEGF therapy is
unlikely to impede their development
FFA showing ghost vessels (yellow
arrow) and retinal collaterals (blue arrow)
in BRVO

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Complication of BRVO:
Neovascularisation
1. Shilling JS, et al. Br J Ophthalmol. 1976;60:810; 2. Henkind P. Aus J Ophthalmol. 1981;9:273–277;
3. Hayreh SS, et al. Ophthalmology. 1983;90:488–506.
• Neovascularisation is the
development of fragile new
vessels, prone to
haemorrhage1,2
– Generally develop in
ischaemic BRVO only3
– Can occur years after
onset3
FFA showing disc neovascularisation
(yellow arrow) and ischaemia (blue arrow)

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Complication of BRVO:
Vitreous haemorrhage
1. Hayreh SS. Indian J Ophthalmol. 1994;42:109–132.
• Bleeding into the vitreous is a late-stage complication of BRVO,
which often occurs secondary to neovascularisation1
Colour fundus
photograph showing
mild vitreous
haemorrhage from
neovascularisation in
superotemporal BRVO

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Long-standing BRVO
Occlusion point
Neovascularisation
Colour fundus photograph and FFA of long-standing BRVO

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Long-standing BRVO
Collateral
vessels
Vascular
leakage

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Long-standing BRVO
Collateral
vessels
Neovascularisation
Venous
sheathing
Neovascularisation

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Natural history and clinical signs: Summary
• Intraretinal haemorrhage, blot haemorrhage and macular oedema
are signs of early-stage BRVO
• Neovascularisation is a complication of BRVO and can lead to
vitreous haemorrhage
• Collateral vessels often open up in long-standing BRVO to
compensate for the occlusion

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Initial management of BRVO

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Diagnosis of BRVO1
BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; IOP = intraocular pressure.
• Medical history
• Ocular investigations
– BCVA
– IOP
• Diagnostic imaging
– Colour fundus photographs
– Optical coherence tomography
– Fundus fluorescein angiography
• Differential diagnosis

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Patients presenting with BRVO should receive tests to
investigate the presence of underlying systemic pathology1
Important tests
to perform
Blood pressure
Fasting lipid test
Serum glucose
Additional tests
Erythrocyte
sedimentation rate
Full blood count

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Management of macular oedema

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Milestones in the medical treatment of macular
oedema secondary to BRVO*
1. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 2. Scott IU, et al. Arch Ophthalmol.
2009;127(9):1115–1128; 3. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 4. Campochiaro PA, et al.
Ophthalmology. 2010;117:1102–1112.e1; 5. Heier JS, et al. Ophthalmology. 2012;119:802–809; 6. Campochiaro PA, et al.
Ophthalmology. 2014;121:209–219; 7. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544.
Laser
Photocoagulation
2004 2007 2010
BVOS1 SCORE2 GENEVA3
Intravitreal
anti-VEGF
2012
1977
Intravitreal
corticosteroids
Treatment first used
Trial data first published
HORIZON5
BRAVO4 RETAIN6
1986 2011 2013
2009 2014 2015
VIBRANT7
*Timeline excludes bevacizumab studies.
2016

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Macular grid laser photocoagulation

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Macular grid laser photocoagulation for BRVO
Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography.
1. Stefansson E. Eur Ophthal Rev. 2009;2:76–79; 2. Branch Vein Occlusion Study Group. Am J Ophthalmol.
1984;98:271–282; 3. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015;
4. Dowler J. J R Soc Med. 2003;96:277–279.
FFS showing laser scars
(arrow) arising from laser
photocoagulation
• Applied in a grid across the macula, avoiding the fovea
• 50–100 µm spot size; 20–100 applications3
• Guided by fluorescein angigraphy2
• Avoid areas of intraretinal haemorrhage2
Technique
• Improves tight junctions in the retinal pigment epithelium1
• Efficacy demonstrated in the Branch Vein Occlusion Study2
Mechanism
• Scarring4
• Loss of central vision4
Side effects

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BVOS: Significant improvement in VA with grid laser
photocoagulation in patients with macular oedema1
1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282.
Follow-up, years
Cumulative
proportion
of
eyes
gaining
≥2
lines
on
two
consecutive
visits,
%
Treated
Control

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Intravitreal corticosteroids

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Intravitreal corticosteroids for BRVO
BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; VEGF = vascular endothelial growth factor.
1. Coscas G, et al. Ophthalmologica. 2011;226:4–28; 2. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128;
3. Haller JA, et al. Ophthalmology. 2011;118:2453–2460.
Fluocinolone
acetonide
(not approved for
use in BRVO)
Triamcinolone
acetonide
(not currently
approved for use
in BRVO)
Intravitreal
dexamethasone
implant
(approved in the UK
for the treatment of
macular oedema
secondary to BRVO
and CRVO)
Mechanism
Postulated to be downregulation of cytokine expression
(including VEGF) to inhibit vascular permeability1
Important side effects include increased intraocular pressure
and cataract formation2,3
Side effects

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Triamcinolone acetonide

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Note
• Triamcinolone is not licensed for the management of
macular oedema secondary to BRVO

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SCORE-BRVO: Study design
NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO.
1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128.
36-month multicentre, randomised clinical trial comparing
intravitreal triamcinolone with grid laser photocoagulation
for macular oedema secondary to BRVO
Triamcinolone every 4 months
1 mg (n = 136) or 4 mg (n = 138)
Grid laser photocoagulation
(n = 137)
Baseline to month 12 (N = 367) (primary outcome; visual acuity gain ≥15 letters)
Continued treatment to month 24 (N = 238)
Continued treatment to month 36 (N = 128)
R
N = 411

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SCORE-BRVO: Patients could receive rescue
treatment if pre-specified criteria were met
BCVA = best-corrected visual acuity.
• Participants could receive rescue treatment if there was
a loss from baseline in BCVA of ≥15 letters that was
present at two consecutive visits
Triamcinolone 4 mg
Triamcinolone 4 mg
Rescue treatment
Initial treatment

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SCORE-BRVO: Inclusion and exclusion criteria
*OCT2 or Stratus OCT. BRVO = branch retinal vein occlusion; CST = central subfield thickness; ETDRS = Early Treatment
Diabetic Retinopathy Study; IOP = intraocular pressure; OCT = optical coherence tomography; VA = visual acuity.
Inclusion criteria Exclusion criteria
• Best-corrected ETDRS visual acuity letter
score of ≤73 (approximate Snellen equivalent,
20/40 or worse) and ≥19 (approximate
Snellen equivalent, 20/400 or better)
• Centre-involved macular oedema secondary
to BRVO present on clinical examination
• Mean CST of 2 OCT* fast macular scans
≥250 μm
• Media clarity, pupillary dilation, and subject
cooperation sufficient for adequate fundus
photographs
• Macular oedema not caused by BRVO
• Ocular condition where VA would not improve
from oedema resolution of the oedema
(e.g., foveal atrophy)
• Cataract reducing VA by ≥3 lines
• Treatment with intravitreal corticosteroids, or
peribulbar steroid injection within 6 months of
randomisation
• History of recent focal/grid macular
photocoagulation, panretinal photocoagulation,
or anticipated need for panretinal
photocoagulation
• Prior pars plana vitrectomy
• Major actual/anticipated ocular surgery (incl.
cataracts)
• IOP ≥25 mmHg, open-angle glaucoma, or
steroid-induced IOP elevation that required
IOP-lowering treatment or pseudoexfoliation
• Aphakia

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SCORE-BRVO: Baseline characteristics were
similar between the treatment groups
NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal
vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; SD = standard deviation.
Characteristic
Macular grid laser
photocoagulation
(n = 137)
Triamcinolone
acetonide 1 mg
(n = 136)
Triamcinolone
acetonide 4 mg
(n = 138)
Demographic characteristics
Mean (SD) age, years
Age range
Female, n (%)
White, n (%)
66.9 (11.5)
22–90
71 (52)
124 (91)
67.2 (11.5)
32–91
68 (50)
115 (85)
68.1 (10.6)
33–94
63 (46)
123 (89)
Study eye characteristics
ETDRS letter score, mean (SD)
73–59 (20/40–20/63), n (%)
58–49 (20/80–20/100), n (%)
48–19 (20/125–20/400), n (%)
56.8 (13.0)
70 (51)
34 (25)
33 (24)
58.2 (11.3)
74 (54)
35 (26)
27 (20)
56.1 (13.4)
71 (51)
33 (24)
34 (25)
Mean duration of macular oedema (SD)
<3 months, n (%)
3–6 months, n (%)
7–12 months, n (%)
>12 months, n (%)
4.5 (4.2)
49 (36)
62 (45)
17 (12)
9 (7)
4.1 (3.4)
52 (38)
63 (46)
18 (13)
3 (2)
4.6 (3.9)
51 (37)
60 (43)
22 (16)
5 (4)
IOP (mmHg), mean (SD)
IOP-lowering medication, n (%)
Phakic, n (%)
15.2 (3.1)
6 (4)
115 (84)
15.0 (2.8)
4 (3)
110 (81)
15.1 (3.1)
3 (2)
110 (80)

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SCORE-BRVO: Baseline characteristics were
similar between the treatment groups (contd.)
BRVO = branch retinal vein occlusion; DA = disc area; ETDRS = Early Treatment Diabetic Retinopathy Study;
OCT = optical coherence tomography; SD = standard deviation.
Characteristic
Macular grid laser
photocoagulation
(n = 137)
Triamcinolone
acetonide 1 mg
(n = 136)
Triamcinolone
acetonide 4 mg
(n = 138)
Other clinical characteristics, n (%)
Diabetes mellitus
Hypertension
Coronary artery disease
History of cancer
18 (13)
99 (72)
20 (15)
24 (18)
17 (13)
93 (68)
27 (20)
24 (18)
24 (17)
95 (69)
28 (20)
30 (22)
Imaging data
OCT centre point thickness (μm),
mean (SD)
Total macular volume (mm3),
mean (SD)
Area of retinal thickening within
the grid (DA)
Area of retinal haemorrhage (DA),
mean (SD)
Area of fluorescein haemorrhage (DA),
mean (SD)
>5 DA of capillary ischaemia in the eye, n (%)
537 (198)
9.6 (1.8)
7.4 (2.7)
3.2 (2.5)
6.2 (2.4)
12 (13)
521 (198)
10.0 (2.1)
7.8 (3.0)
2.8 (2.3)
6.2 (2.3)
17 (18)
516 (160)
9.5 (1.6)
7.4 (2.8)
2.9 (2.4)
6.0 (2.5)
12 (12)
Non-study eye ETDRS letter score, mean (SD) 81.9 (13.2) 83.7 (8.6) 81.9 (10.7)

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SCORE-BRVO: Triamcinolone offers similar
benefit to grid laser1
BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study.
Mean gain from baseline
in ETDRS letters was
4.2, 5.7 and 4.0 letters,
for macular grid laser
photocoagulation,
triamcinolone acetonide
1 mg and triamcinolone
acetonide 4 mg,
respectively (p=0.70)
Macular grid laser
photocoagulation
(n = 121)
Triamcinolone
acetonide 1 mg
(n = 121)
Triamcinolone
acetonide 4 mg
(n = 125)
Proportion
of
patients
gaining
≥15
letters
at
12
months
(%)
Proportion of patients gaining ≥15 letters
(primary outcome)
Mean no. treatments to month 12 1.5 2.2 2.1
No. patients receiving rescue treatment 4 7 3

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SCORE-BRVO: Higher adverse event rates with
triamcinolone versus grid laser1
*Standard care vs 1-mg group, p=0.03; standard care vs 4-mg group, p<0.001; and 1-mg vs 4-mg group, p<0.001.
**Standard care vs 1-mg group, p=0.03; standard care vs 4-mg group, p<0.001; and 1-mg vs 4-mg group, p=0.10.
BRVO = branch retinal vein occlusion; IOP = intraocular pressure.
Safety through
12 months
Macular grid laser
photocoagulation
(n = 137)
Triamcinolone
acetonide
1 mg
(n = 136)
Triamcinolone
acetonide
4 mg
(n = 138)
Initiation of IOP-lowering
medication* (%)
2 8 41
Lens opacity onset
or progression** (%)
13 25 35
Other ocular adverse
events (%)
8 4 8

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SCORE-BRVO: Summary
• Patients were randomised to triamcinolone acetonide
1 mg, triamcinolone acetonide 4 mg, or macular grid
laser photocoagulation
• Triamcinolone acetonide (1 mg and 4 mg) demonstrated
similar efficacy to grid laser for the treatment of macular
oedema secondary to BRVO
• Triamcinolone acetonide 4 mg was associated with
higher rates of adverse events versus triamcinolone
acetonide 1 mg and laser

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Intravitreal dexamethasone implant

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Note
• The dose and dosing regimen for dexamethasone used
in the GENEVA study does not necessarily represent
its current recommended posology. Please consult the
dexamethasone Summary of Product Characteristics
for further details

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GENEVA: Study design
†Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does
not necessarily represent its current recommended posology. DEX = dexamethasone; RVO = retinal vein occlusion.
1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 2. Haller JA, et al. Ophthalmology. 2011;118:2453–2460.
12-month, phase 3, multicentre, double-masked, trial of treatment
with dexamethasone intravitreal implant (DEX)
for macular oedema with BRVO or CRVO
Single DEX implant or sham injection at Day 0 (masked treatment)1
Open-label treatment to month 122
At day 180, n = 997
DEX implant 0.7 mg†
(n = 427)
DEX implant 0.35 mg
(n = 414)
Sham
(n = 426)
R
N = 1267

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GENEVA: Retreatment with DEX 0.7 mg at day 180
if one of the following criteria were met
*OCT2 or OCT3.
BCVA = best-corrected visual acuity; DEX = dexamethasone; OCT = optical coherence tomography.
1. Haller JA, et al. Ophthalmology. 2011;118:2453–2460
BCVA <84 letters (20/20)
Retinal thickness >250 µm in the central
1-mm macular subfield as measured by OCT*
Procedure would not put patient at significant risk
(Investigator's opinion)

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GENEVA: Inclusion and exclusion criteria
*OCT2 or OCT3.
BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion;
CST = central subfield thickness; IOP = intraocular pressure; OCT = optical coherence tomography; VA = visual acuity.
• Decreased VA as a result of clinically detectable
macular oedema associated with CRVO
(6 weeks to 9 months duration) or BRVO
(6 weeks to 12 months duration)
• BCVA 34 to 68 letters (approximately 20/200 and
20/50 Snellen equivalent)
• CST ≥300 μm by OCT*
• Presence of clinically significant epiretinal
membrane, active retinal or optic disc
neovascularisation
• Active or history of choroidal neovascularisation
• Presence of rubeosis iridis
• Active infection, aphakia or anterior-chamber
intraocular lens, clinically significant media opacity,
glaucoma or current ocular hypertension requiring
>1 medication to control IOP in the study eye,
or a history of steroid-induced IOP increase in
either eye
• Diabetic retinopathy in either eye
• Uncontrolled systemic disease
• Current/anticipated use of systemic
steroids/anticoagulants
• Any ocular condition in the study eye that would
prevent a 15-letter improvement in visual acuity

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GENEVA: Baseline characteristics were similar
across the treatment groups
†Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not
necessarily represent its current recommended posology. DEX = dexamethasone; ETDRS = Early Treatment Diabetic
Retinopathy Study; IOP = intraocular pressure; SD = standard deviation.
Characteristic
DEX implant
0.7 mg†
(n = 427)
DEX implant
0.35 mg
(n = 414)
Sham
(n = 426)
Mean (range) age, years
Male, n (%)
White, n (%)
64.7 (33–90)
217 (50.8)
321 (75.2)
64.9 (31–96)
220 (53.1)
312 (75.4)
63.9 (31–91)
240 (56.3)
318 (74.6)
ETDRS letter score, mean (SD) 54.3 (9.93) 53.9 (10.41) 54.8 (9.86)
Duration of macular oedema, n (%)
Mean duration (range)
<90 days
90–179 days
180–269 days
≥270 days
157.6 (19–374)
70 (16.4)
219 (51.3)
93 (21.8)
45 (10.5)
153.0 (49–944)
76 (18.1)
218 (52.7)
89 (21.5)
32 (7.7)
156.1 (19–374)
65 (15.3)
220 (51.6)
99 (23.2)
42 (9.9)
IOP-lowering medication, n (%) 27 (6) 24 (6) 16 (4)
Phakic, n (%) 373 (88) 362 (87) 387 (91)
Retinal thickness (μm), mean (SD) 562 (188) 555 (204) 539 (186)

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GENEVA: Baseline characteristics were similar
necessarily represent its current recommended posology.
BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; DEX = dexamethasone.
Characteristic
DEX implant
0.7 mg†
(n = 427)
DEX implant
0.35 mg
(n = 414)
Sham
(n = 426)
Other clinical characteristics, n (%)
Diabetes mellitus
Hypertension
Coronary artery disease
64 (15)
264 (62)
55 (13)
57 (14)
264 (64)
49 (12)
63 (15)
273 (64)
38 (9)
Prior laser photocoagulation, n (%)
BRVO
CRVO
41 (10)
37 (90)
4 (10)
44 (11)
40 (91)
4 (9)
40 (9)
36 (90)
4 (10)
Other procedures for RVO, n (%)
Haemodilution
Intraocular injection
1 (0.2)
0
1 (0.2)
1 (0.2)
2 (0.5)
1 (0.2)

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GENEVA: At day 180, proportion of eyes gaining ≥15 letters
from baseline with DEX not significantly different from sham1
†Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does
not necessarily represent its current recommended posology. *p<0.001; **p=0.006; ***p=0.013 versus sham.
DEX = dexamethasone.
Proportion
of
eyes
gaining
≥15
letters
(%)
Dexamethasone implant 0.7 mg† (n = 291)
Dexamethasone implant 0.35 mg (n = 260)
Sham (n = 279)
Study day
Proportion of BRVO patients gaining ≥15 letters at day 180
(primary outcome)

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GENEVA: Improvements in BCVA peak at day 60
with DEX1
†Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study
does not necessarily represent its current recommended posology.
BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; DEX, dexamethasone.
Time post-treatment (days)
Mean
change
in
BCVA
from
baseline
(letters)
*p=0.008 versus sham
**p<0.001 versus sham
Dexamethasone implant 0.7 mg† (n = 291)
Dexamethasone implant 0.35 mg (n = 260)
Sham (n = 279)
Mean change in BCVA in BRVO patients
(secondary outcome)

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GENEVA: Incidence of ocular AEs is higher
in DEX groups versus sham1,2
necessarily represent its current recommended posology. *At day 180, patients could receive DEX implant 0.7 mg if BCVA was
<84 letters or retinal thickness was >250 µm. AE = adverse event; BRVO = branch retinal vein occlusion; CRVO = central
retinal vein occlusion; DEX = dexamethasone; IOP = intraocular pressure.
1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 2. Haller JA, et al. Ophthalmology. 2011;118:2453–2460.
• Excluding cataract, the ocular AE profile was similar at day 180 and 3602
• In phakic eyes, cataract formation was observed in more re-treated eyes*
(29.8%) than delayed-treatment eyes (10.5%; p<0.001)2
Characteristic
DEX implant
0.7 mg†
(n = 421)
DEX implant
0.35 mg
(n = 412)
Sham
(n = 423)
P-value versus
sham
0.35 mg/0.7 mg
Ocular AEs, % 62.9 61.9 42.8 p<0.001
Conjunctival haemorrhage, n (%) 85 (20.2) 72 (17.5) 63 (14.9) NS
Eye pain, n (%) 31 (7.4) 17 (4.1) 16 (3.8) P=0.023/NS
Conjunctival hyperaemia, n (%) 28 (6.7) 27 (6.6) 20 (4.7) NS
Cataract, n (%) 31 (7.3) 17 (4.1) 23 (5.4) NS
Maculopathy, n (%) 19 (4.5) 22 (5.3) 23 (5.4) NS
Increased IOP ≥10 mmHg, % 16% (pooled) 0 p<0.001

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GENEVA: Summary
AEs = adverse events; DEX = dexamethasone; RVO = retinal vein occlusion.
• GENEVA compared DEX intravitreal implant 0.7 mg and
0.35 mg with sham for the treatment of macular oedema
secondary to BRVO and CRVO
• A significantly greater proportion of BRVO patients
gained ≥15 letters with DEX (0.35 mg and 0.7 mg)
versus sham at days 30, 60, and 90
– However, this difference was not maintained to day 180
• At day 180, incidence of ocular AEs was higher in BRVO
patients in the DEX groups (0.7 mg and 0.35 mg) versus
sham
• Repeat dosing with DEX increased cataract formation

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Anti-VEGF therapy

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Intravitreal anti-VEGF therapies block the actions
of VEGF to alleviate symptoms of BRVO
Mechanism
Anti-VEGF therapies when injected into
the eye block the actions of VEGF. This
reduces vascular leakage and macular
oedema and inhibits the growth of the
blood vessels located within the eye1,2
Intravitreal injection of
anti-VEGF agents
Macular
oedema
Ciliary
body
Cornea
Limbus
Ora serrata
1. Rehak J, et al. Curr Eye Res. 2008;33:111–131; 2. Mitry D, et al. Coch Database Syst Rev. 2013;1:CD009510;
3. Heier JS, et al. Ophthalmology. 2012;119:802–809; 4. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544.
Side effects3,4
Systemic side effects:
• Nasopharyngitis, hypertension
Ocular side effects:
• Conjunctival haemorrhage, retinal
haemorrhage
Side effects are rare. The most common
side effects are those associated with
intravitreal injections

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Intravitreal anti-VEGF treatments for BRVO
BRVO = branch retinal vein occlusion; PlGF = placental growth factor; VEGF = vascular endothelial growth factor.
1. EYLEA Summary of Product Characteristics; 2. EYLEA Prescribing Information; 3. Lucentis: EPAR Scientific Discussion
2007; 4. Avastin Prescribing Information 2014; 5. Avery RL, et al. Br J Ophthalmol. 2014;98:1636–1641.
Bevacizumab Ranibizumab
Aflibercept
Affinity
maturation
Two ranibizumab
molecules can bind
each VEGF dimer
Anti-VEGF Structure
Size
(kDa)
Target(s)
Systemic
half-life
Fc portion
Aflibercept1,2 Recombinant fusion
protein
97–115 VEGF-A and PlGF 5–6 days Yes
Ranibizumab3 Antibody fragment 48 VEGF-A Approx. 2 h No
Bevacizumab4,5 Recombinant humanised
monoclonal antibody
149 VEGF-A 20 days Yes
Not licensed for intravitreal use

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Bevacizumab

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Note
• Bevacizumab is not licensed for intraocular use

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Bevacizumab is unlicensed in BRVO
1. Russo V. Retina. 2009;29(4):511–515; 2. Prager F. Br J Ophthalmol. 2009;93(4):452–456; 3. Moradian S.
Graefes Arch Clin Exp Ophthalmol. 2011;249(2):193–200; 4. Leitritz MA. Br J Ophthalmol. 2013;97(2):215–219;
5. Hikichi T. Br J Ophthalmol. 2014;98(2):195–199.
• There are no large randomised controlled trials for
bevacizumab in BRVO
Study Study type Number of patients Endpoint
Russo, 20091 Prospective,
randomised study
Bevacizumab: 15
Grid laser: 15
12 months
Prager, 20092 Prospective clinical trial Bevacizumab: 21 (eyes) 12 months
Moradian, 20113 Prospective,
randomised clinical trial
Bevacizumab: 42
Sham: 39
12 weeks
Leitritz, 20134
Prospective
interventional
case series
Bevacizumab: 23
Grid laser: 21
1 year
Hikichi, 20145 Single-arm trial Bevacizumab: 105 2 years

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Ranibizumab

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Note
• The dosing regimen for ranibizumab used in the BRAVO-
HORIZON-RETAIN studies does not represent its current
recommended treatment frequency, which varies
according to response. Please consult the ranibizumab
Summary of Product Characteristics for further details
• The 0.3 mg dose of ranibizumab is not licensed in
the UK

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Efficacy of ranibizumab in BRVO:
The BRAVO-HORIZON-RETAIN studies
NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended
treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Primary efficacy outcome was mean change in BCVA.
BRVO = branch retinal vein occlusion; PRN = pro re nata (as needed); R = randomised.
1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Heier JS, et al. Ophthalmology. 2012;119:802–809;
3. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219.
60
48
0.5 mg monthly
PRN for
12 months then
3-monthly PRN
(n = 34)
RETAIN3
BRAVO primary
outcome*
HORIZON primary
outcome*
RETAIN primary
outcome*
Patients with
macular
oedema
secondary to
BRVO
0.3 mg monthly
(n = 134)
Sham monthly
(n = 132)
0.5 mg monthly
(n = 131)
0.3 mg
monthly PRN
0.5 mg
monthly PRN
0.5 mg
monthly PRN
Baseline 6 12
R
BRAVO1
24 36
0.5 mg
3-monthly PRN
(n = 103)
0.5 mg
3-monthly PRN
(n = 104)
0.5 mg
3-monthly PRN
(n = 97)
HORIZON2
Time (months)

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BRAVO: Ranibizumab in the treatment
of macular oedema secondary to BRVO1
NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent
its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK.
*Re-treatment was based on BCVA ≤20/40 or mean CST ≥250 µm. BCVA = best-corrected visual acuity;
BRVO = branch retinal vein occlusion; CST = central subfield thickness; PRN = pro re nata (as needed); R = randomised.
1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1.
Patients with
macular
oedema
secondary
to BRVO
0.3 mg monthly
(n = 134)
Sham monthly
(n = 132)
0.5 mg monthly
(n = 131)
0.3 mg monthly
PRN*
0.5 mg monthly
PRN*
0.5 mg monthly
PRN*
Baseline 6
R
BRAVO
12
Primary outcome
(Mean change in BCVA from baseline to 6 months)
Time (months)

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BRAVO: At month 3, patients became eligible for rescue
laser photocoagulation if they met the following criteria
BCVA = best-corrected visual acuity; CST = central subfield thickness; OCT = optical coherence tomography.
Haemorrhages had cleared sufficiently to
allow safe application of laser
Snellen equivalent BCVA ≤20/40 or mean
CST ≥250 µm on OCT
Gain of <5 letters in BCVA from or decrease
of <50 µm in mean CST in past 3 months

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BRAVO: Inclusion and exclusion criteria
*Stratus OCT.
AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion;
CVA = cerebrovascular accident; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study;
MI = myocardial infarction; OCT = optical coherence tomography; RVO = retinal vein occlusion;
VEGF = vascular endothelial growth factor.
• Age ≥18 years of age
• Foveal centre-involved macular oedema
secondary to BRVO diagnosed within 12 months
before study initiation
• BCVA 20/40 to 20/400 Snellen equivalent using
the ETDRS charts (letter score ≤73 to ≥19)
• Mean CST ≥250 µm from two OCT*
measurements
• Prior episode of RVO
• Brisk afferent pupillary defect (i.e., obvious and
unequivocal)
• >10-letter improvement in BCVA between
screening and day 0
• Recent intraocular corticosteroid use in study eye
• History of radial optic neurotomy or sheathotomy
• History or presence of wet or dry AMD
• Recent panretinal scatter photocoagulation or
sector laser photocoagulation.
• Evidence upon examination of any diabetic
retinopathy
• CVA or MI within 3 months before day 0
• Recent anti-VEGF treatment in study or fellow eye
or systemic anti-VEGF pro-VEGF treatment

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BRAVO: Baseline characteristics were similar
NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK.
ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; SD = standard deviation.
Characteristic
Ranibizumab
0.3 mg
(n = 134)
Ranibizumab
0.5 mg
(n = 131)
Sham
(n = 132)
Mean (SD) age, years
Age range
Male, n (%)
White, n (%)
66.6 (11.2)
43–90
67 (50.0)
112 (83.6)
67.5 (11.8)
41–91
71 (54.2)
107 (81.7)
65.2 (12.7)
26–89
74 (56.1)
108 (81.8)
Months since diagnosis, n (%)
Mean (range)
≤3 months
>3 to ≤6 months
>6 to ≤9 months
>9 to ≤12 months
>12 months
3.6 (0–35)
85 (63.4)
29 (21.6)
9 (6.7)
8 (6.0)
3 (2.2)
3.3 (0–13)
88 (67.2)
20 (15.3)
14 (10.7)
7 (5.3)
2 (1.5)
3.7 (0–16)
85 (64.4)
17 (12.9)
12 (9.1)
16 (12.1)
2 (1.5)
IOP (mmHg), mean (SD)
IOP-lowering medication, n (%)
Phakic, n (%)
15.0 (3.3)
20 (14.9)
103 (85.1)
14.9 (3.3)
16 (12.2)
94 (80.3)
14.8 (3.0)
10 (7.6)
93 (78.8)

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Characteristic
Ranibizumab
0.3 mg
(n = 134)
Ranibizumab
0.5 mg
(n = 131)
Sham
(n = 132)
Imaging data
CFT (μm), mean (SD) 522.1 (201.9) 551.7 (223.5) 488.0 (192.2)
Total macular volume (mm3),
mean (SD)
9.6 (1.8) 9.8 (2.2) 9.6 (1.8)
Area of retinal haemorrhage (DA),
mean (SD)
0.1 (0.1) 0.1 (0.1) 0.1 (0.1)
Area of fluorescein leakage within the
grid (DA), median (%)
6 7 7
>10 DA of capillary non-perfusion (%) 0 0 0
Non-study eye ETDRS letter score,
mean (SD)
79.4 (13.7) 81.4 (13.8) 79.8 (17.4)
BRAVO: Baseline characteristics were similar
across the treatment groups (contd.)
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. CFT = central foveal thickness;
DA = disc areas; ETDRS = Early Treatment Diabetic Retinopathy Study; SD = standard deviation.

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BRAVO: Ranibizumab rapidly and significantly
improves BCVA in BRVO1,2
treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *p<0.0001 versus sham; **p<0.01 versus
sham/0.5 mg. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; PRN = pro re nata (as needed).
1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Brown DM, et al. Ophthalmology. 2011;118:1594–1602.
Day 0–Month 5
monthly treatment
Months 6–11
PRN treatment
Ranibizumab 0.5 mg (n = 131)
Sham/ranibizumab 0.5 mg (n = 132)
Mean
change
in
BCVA
from
baseline
(ETDRS
letters)
Day 7
Time (months)
Mean change in BCVA (primary outcome)
Day 0–Month 5 Months 6–11
0.5 mg 0.3 mg Sham 0.5 mg 0.3 mg Sham
Mean no. treatments 5.7 5.7 5.5 2.7 2.8 3.6
% patients receiving rescue laser 21.4 20.1 57.6 23.7 30.6 23.5

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BRAVO: The majority of patients receiving
ranibizumab gained ≥15 letters at month 61
NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent
its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK.
Percentage of patients who gained and lost letters at month 6
Percentage
of
patients
(%)
Sham (n = 132)
Vision gain Vision loss
No change 5–9
letters
10–14
letters
≥15
letters
5–9
letters
10–14
letters
≥15
letters

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BRAVO: Ranibizumab rapidly and significantly
reduces CFT from baseline in BRVO1,2
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *p<0.0001; **p<0.05 versus sham.
The last observation carried forward method was used to impute missing values. BRVO = branch retinal vein occlusion;
CFT = central foveal thickness; PRN = pro re nata (as needed).
1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Brown DM, et al. Ophthalmology. 2011;118:1594–1602.
Mean
change
in
CFT
from
baseline
(μm)
Sham/ranibizumab 0.5 mg (n = 132)
*
Mean change in CFT (secondary outcome)
Day 0–Month 5
monthly treatment
Months 6–11
PRN treatment
Time (months)
Day 7

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BRAVO: Safety to month 12
1. Brown DM, et al. Ophthalmology. 2011;118:1594–1602.
Safety
Ranibizumab
0.3 mg
(n = 134)
Ranibizumab
0.5 mg
(n = 130)
Sham
(day 0 to month 6)
(n = 131)
Sham/ranibizumb 0.5 mg
(months 6 to 12)
(n = 115)
Ocular AEs
Intraocular inflammation 3 (2.2) 0 4 (3.1) 1 (0.9)
Vitreous haemorrhage 7 (5.2) 2 (1.5) 6 (4.6) 1 (0.9)
Cataract 6 (4.5) 8 (6.2) 4 (3.1) 3 (2.6)
Endophthalmitis 0 1 (0.8) 0 0
Lens damage 0 0 0 0
Iris neovascularization 1 (0.7) 1 (0.8) 3 (2.3) 0
Neovascular glaucoma 0 0 0 0
Rhegmatogenous retinal
detachment
1 (0.7) 0 0 0
Retinal tear 1 (0.7) 0 0 0
Non-ocular SAEs
SAEs potentially related to
VEGF inhibition
6 (4.5) 6 (4.6) 1 (0.8) 2 (1.7)
APTC ATEs 1 (0.7) 2 (1.5) 1 (0.8) 1 (0.9)
Death 0 0 0 0

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HORIZON: Extension study evaluating the efficacy
and safety of ranibizumab in BRVO1
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Primary outcome recorded;
†Re-treatment was based on BCVA ≤20/40 or mean CST ≥250 µm; ‡Re-treatment was based on CST ≥250 µm or persistent or
recurrent macular oedema deemed to be affecting the patient’s VA (according to the investigator). ¶Rescue macular grid laser
photocoagulation could be administered if patients had BCVA ≤20/40 caused by macular oedema. BCVA = best-corrected
visual acuity; BRVO = branch retinal vein occlusion; CST = central subfield thickness; PRN = pro re nata; R = randomised.
1. Heier JS, et al. Ophthalmology. 2012;119:802–809.
Patients with
macular
oedema
secondary
to BRVO
completing
BRAVO
0.3 mg
monthly
(n = 134)
Sham monthly
(n = 132)
0.5 mg
monthly
(n = 131)
0.3 mg
monthly
PRN†
0.5 mg
monthly
PRN†
0.5 mg
monthly
PRN†
Baseline 6 12
(n = 304)
R
BRAVO
24
(n = 205)
36*
(n = 2)
0.5 mg
3-monthly PRN‡
(n = 103)
0.5 mg
3-monthly PRN‡
(n = 104)
0.5 mg
3-monthly PRN‡
(n = 97)
HORIZON¶
Trial termination
Time (months)

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HORIZON enrolled patients who completed BRAVO
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. CFT = central foveal thickness;
ETDRS = Early Treatment Diabetic Retinopathy Study; RVO = retinal vein occlusion; SD =standard deviation.
Characteristic
Ranibizumab
0.3 mg/0.5 mg
(n = 103)
Ranibizumab
0.5 mg
(n = 104)
Sham/
ranibizumab 0.5 mg
(n = 97)
Mean (SD) age, years 67.7 (11.3) 68.3 (12.3) 66.2 (12.2)
Male, n (%) 46 (44.7) 58 (55.8) 54 (55.7)
White, n (%) 86 (83.5) 84 (80.8) 82 (84.5)
CFT, mean (SD), µm 208.5 (144.9) 187.0 (80.8) 196.7 (107.4)

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HORIZON: Ranibizumab maintained BCVA
improvements achieved in BRAVO
*Due to early termination of the study, HORIZON efficacy analyses (secondary outcomes) were presented for 24 rather
than 36 months. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion.
BRAVO baseline
Time (months)
Mean
change
in
BCVA
from
BRAVO
baseline
BRAVO HORIZON
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg/0.5 mg
Sham/0.5 mg ranibizumab
12 15 18 21 24*
Mean change in BCVA
(primary outcome)
Mean no. injections at month 24 2.1 2.4 2.0
Patients receiving rescue laser, n (%) 5 (7) 4 (6) 3 (5)
n = 104 (0.5 mg)
n = 103 (0.3 mg)
n = 97 (sham)
n = 66 (sham/0.5 mg)
n = 66 (0.3 mg/0.5 mg)
n = 73 (0.5 mg)

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HORIZON: No new safety events reported with
long-term use of ranibizumab in BRVO1
recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. Safety analyses included all
patients over the entire study duration (up to 24 months).
Ranibizumab
0.3/0.5 mg
(n = 66)
Ranibizumab
0.5/0.5 mg
(n = 73)
Sham/
ranibizumab 0.5 mg
(n = 66)
Ocular AEs (% patients)
Retinal haemorrhage 24.3 21.2 11.8
Conjunctival haemorrhage 20.4 14.4 15.1
Cataract 9.7 5.8 6.5
Non-ocular AEs, n (%)
Hypertension 15 (14.6) 9 (8.7) 8 (8.6)
Nasopharyngitis 6 (5.8) 1 (1.0) 7 (7.5)
APTC-defined ATEs, n (%) 1 (1.0) 4 (3.8) 1 (1.1)
Death, n (%) 0 2 (2.0) 0

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Patients
with
macular
oedema
secondary
to BRVO
completing
HORIZON
0.3 mg
monthly
(n = 134)
Sham
monthly
(n = 132)
0.5 mg
monthly
(n = 131)
0.3 mg
monthly
PRN‡
0.5 mg
monthly
PRN‡
0.5 mg
monthly
PRN‡
Baseline 6 12
R
BRAVO
24*
(n = 205)
36
0.5 mg
3-monthly PRN
(n = 103)§
0.5 mg
3-monthly PRN
(n = 104)§
0.5 mg
3-monthly PRN
(n = 97)§
HORIZON
60
(n = 26)
48†
RETAIN: Further extending evaluation
of ranibizumab in BRVO1
treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Due to early termination of the study, HORIZON efficacy
analyses (secondary outcomes) were presented for 24 months rather than 36 months. †Mean BCVA was recorded for all patients enrolled in
the BRAVO trial baseline and every 6 months thereafter through 48 months for all patients enrolled in the RETAIN study. ‡Re-treatment was
based on BCVA ≤20/40 or mean CST ≥250 µm. §Re-treatment was based on CST ≥250 µm or persistent or recurrent macular oedema
deemed to be affecting the patient’s VA (according to the investigator). ‖9% of BRAVO population; re-treatment was based on intravitreal fluid
involving the fovea. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CST = central subfield
thickness; PRN = pro re nata; R = randomised; VA = visual acuity.
0.5 mg monthly
PRN for
12 months then
3-monthly PRN
(n = 34)‖
RETAIN
Primary outcome
(Mean improvement in BCVA)
Time (months)

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Patients in RETAIN had similar characteristics at
BRAVO baseline to the rest of the BRAVO population
BCVA = best-corrected visual acuity; CFT = central foveal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study.
1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219; 2. Campochiaro PA, et al. Ophthalmology. 2010;117:
1102–1112.e1.
• Only 9% of the BRAVO population entered RETAIN
Characteristic at BRAVO
baseline
RETAIN1
(n = 34)
BRAVO2
(n = 397)
Mean age, years 63.9 66.4
Mean BCVA, ETDRS letter score 54.0 54.6
Mean CFT, µm 465.9 520.5

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RETAIN: For some patients BRVO is a chronic
condition, requiring long-term treatment1
For all patients enrolled in the RETAIN study, mean BCVA was recorded at BRAVO trial baseline and every 6 months
thereafter throughout HORIZON up to the end of RETAIN at 48 months.
BCVA = best-corrected visual acuity.
• 50% of BRVO patients did not have resolution of macular
oedema (mean follow-up 50.2 months)
– These patients required an average of 3 injections during
last year of follow-up in RETAIN
D0–M5
M6–
M11
M12–
M17
M18–
M23
M24–
M29
M30–
M35
M36–
M41
M42–
M47
n 34 34 34 34 34 33 30 28
Mean number
of injections
4.2 3.1 1.3 1.3 1.0 1.1 1.1 0.9
BRAVO HORIZON RETAIN

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• BCVA improvement of ≥15 letters was observed in 61.8% of patients
in RETAIN
RETAIN: Improvements in BCVA in BRAVO
were maintained for patients enrolled in RETAIN1
Blue arrows indicate time of assessment of primary outcomes (RETAIN: mean improvement in BCVA and patients [%] with
oedema resolution). BCVA = best-corrected visual acuity.
34
Mean ETDRS letter score (secondary outcome)
Mean
ETDRS
letter
score
BRAVO RETAIN
HORIZON
34
Mean change 20.1
letters from BRAVO
baseline (primary
outcome)

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BRAVO-HORIZON-RETAIN: Summary
• The BRAVO-HORIZON-RETAIN trials aimed to assess the efficacy of
ranibizumab for the treatment of macular oedema secondary to BRVO
• Ranibizumab rapidly and significantly improved BCVA and CRT versus
sham at month 12
– These results were maintained to month 24
• Only 9% of the BRAVO population entered RETAIN
– No firm conclusions can be made on the long-term efficacy of ranibizumab
• For some patients, BRVO is a chronic condition requiring long-term
treatment
– 50% of patients still required treatment at mean follow-up 50.3 months
• No new safety events occurred with the long-term use
of ranibizumab

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Aflibercept

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Note
• The dosing regimen of aflibercept used in VIBRANT
does not necessarily reflect the licensed posology,
please refer to the summary of product characteristics for
more details.

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52-week double-masked, randomised, active-controlled study to assess
the efficacy and safety of intravitreal aflibercept versus laser treatment
in patients with macular oedema secondary to BRVO or HRVO
VIBRANT trial design1,2
BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRT = central retinal thickness; ETDRS = Early
Treatment Diabetic Retinopathy Study; NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire.
1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. https://clinicaltrials.gov/ct2/show/NCT01521559.
Aflibercept
Macular laser
photocoagulation
N = 183
R
Proportion of eyes that gained ≥15 ETDRS letters in BCVA from baseline at week 24
Primary outcome
Change from baseline in BCVA, CRT and NEI VFQ-25 total scores at week 24
Secondary outcomes

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VIBRANT: Inclusion and exclusion criteria
BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic
Retinopathy Study.
1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. https://clinicaltrials.gov/ct2/show/NCT01521559.
• Adults ≥ 18 years of age
• Foveal centre-involved macular oedema secondary
to BRVO or HRVO diagnosed within 12 months
before the screening visit
• ETDRS BCVA letter score of 73 to 24 (20/40 to
20/320) in the study eye at screening and at day 1
• Current bilateral manifestation of BRVO
• Uncontrolled glaucoma defined as ≥25 mmHg on
optimal medical regimen, or previous filtration surgery
in either the study eye or the fellow eye
• Insufficient clearing of macular haemorrhage that
would prevent the patient from receiving laser
treatment safely on day 1
• Uncontrolled diabetes mellitus
• Previous use of intraocular corticosteroids or anti-
angiogenic drugs in the study eye
• Recent use of periocular corticosteroids in the study
eye
• Recent use of intraocular or periocular corticosteroids
or anti-angiogenic drugs in the fellow eye
• Previous administration of systemic anti-angiogenic
medications
• Panretinal scatter photocoagulation, sector laser
photocoagulation, or macular grid photocoagulation in
the study eye

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VIBRANT: Scheduled dosing (excluding rescue)1,2*
*Rescue dosing schedule detailed on subsequent slides.
2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BRVO = branch retinal vein occlusion.
1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336.
Baseline
Aflibercept
Laser
Week
Primary outcome
Secondary outcomes
End of study
assessments
Patients
with BRVO
randomised 1:1
Aflibercept 2q4
Sham aflibercept
Active laser
Sham laser
Aflibercept 2q8

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VIBRANT: Patients who met one or more of the eligibility
criteria could receive rescue treatment from week 12
BRVO = branch retinal vein occlusion; CRT = central retinal thickness; OCT = optical coherence tomography.
• Patients in laser arm:
– At weeks 12, 16 and 20 option
to receive laser rescue
– From week 24, option to
receive aflibercept 2 mg
rescue (3 x 2q4 followed
by 2q8)
• Patients in aflibercept arm:
– At week 36, option to receive
laser rescue
• Masking was maintained up to
week 52 using sham injection
and sham laser
>50 μm increase in CRT compared with the
lowest previous measurement
New or persistent cystic retinal changes,
sub-retinal fluid, or persistent diffuse
oedema in the central OCT subfield
Loss of ≥5 letters compared with the best
previous measurement because of BRVO in
conjunction with any increase in CRT

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VIBRANT is the first phase III anti-VEGF clinical trial
to include ischaemic BRVO patients
BRVO = branch retinal vein occlusion CRVO = central retinal vein occlusion.
1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol.
1986;104:34–41; 3. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.
• Definition of ‘ischaemic BRVO’ varies between studies
– In VIBRANT: ≥10 disc areas of retinal capillary
non-perfusion1
– In BVOS: >5 disc diameters of retinal capillary
non-perfusion2
• BRAVO did not include patients with ischaemic BRVO3
– Patients with brisk afferent pupillary defect were excluded

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VIBRANT: Rescue treatment schedule1,2
Dashed outline represents an opportunity for rescue treatment; †Rescue laser ≥12 weeks apart from the last laser treatment;
‡Subjects in the laser arm eligible for rescue aflibercept treatment starting at week 24, and received three aflibercept 2q4 injections,
followed by aflibercept 2q8. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BRVO = branch retinal vein occlusion.
1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544. 2. Clark WL, et al. Ophthalmology. 2016;123:330–336.
Baseline
Aflibercept
Laser
Week
Primary outcome
Secondary outcomes
End of study
assessments
Patients
with BRVO
randomised 1:1
Active laser
Sham laser
Rescue treatment
Aflibercept + rescue
treatment
Laser + rescue treatment
Aflibercept 2q4
Sham aflibercept
Aflibercept 2q8

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VIBRANT: Baseline demographics and disease
characteristics were balanced between treatment arms1
Full analysis set.
*<10 disc areas of retinal
capillary non-perfusion.
**≥10 disc areas of retinal
capillary non-perfusion.
†BCVA data not available for
2/92 randomised patients.
BCVA = best-corrected visual
acuity; BRVO = branch
retinal vein occlusion;
CRT = central retinal
thickness; SD = standard
deviation.
Laser
(n = 90)†
Aflibercept
(n = 91)
Mean age, years (SD) 63.9 (11.4) 67.0 (10.4)
Women, n (%) 36 (40.0) 47 (51.6)
Race [white], n (%) 62 (68.9) 70 (76.9)
BCVA
Mean, letters (SD) 57.7 (11.3) 58.6 (11.4)
>20/200 (35‒73 letters), n (%) 83 (92.2) 85 (93.4)
≤20/200 (24‒34 letters), n (%) 7 (7.8) 6 (6.6)
Retinal perfusion status, n (%)
Perfused* 62 (68.9) 55 (60.4)
Non-perfused** 16 (17.8) 20 (22.0)
Cannot grade 10 (11.1) 16 (17.6)
Missing 2 (2.2) 0
Mean CRT, μm (SD) 553.5 (188.1) 558.9 (185.9)
Time since BRVO diagnosis
Mean, days (SD) 43.1 (38.8) 42.4 (43.4)
<3 months, n (%) 72 (80.0) 75 (82.4)
≥3 months, n (%) 11 (12.2) 7 (7.7)
Missing, n (%) 7 (7.8) 9 (9.9)

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VIBRANT: Fewer patients given aflibercept vs laser
photocoagulation required rescue treatment1,2
Baseline to
week 24
Week 24 to
week 52
Baseline to
week 52
Aflibercept arm
Mean number of aflibercept injections 5.7 9.0
Patients receiving rescue laser, n (%) 9 (10.6)
Laser arm
Mean number of laser treatments received 1.7
Mean number of rescue AFL injections
received
4.4
Patients receiving rescue AFL injections,
n (%)
67 (80.7)

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VIBRANT: Significantly more eyes gained ≥15 ETDRS
letters with aflibercept vs laser therapy1,2
Full analysis set. Missing data imputed using the last observation carried forward method.*p=0.0003 versus laser; **p=0.0296
versus laser. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; ETDRS = Early Treatment Diabetic Retinopathy Study.
Laser
(n = 90†)
Aflibercept
2q4 (n = 91)
Aflibercept
2q8 (n = 91)
Laser + rescue
aflibercept
(n = 90†)
0–24 weeks 24–52 weeks
Proportion
of
patients
who
gained
≥15
letters
from
baseline
(%)
Proportion of patients gaining ≥15 letters
(primary outcome)

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VIBRANT: Gains in BCVA were rapid and sustained
to 52 weeks in eyes treated with aflibercept1,2
Full analysis set. Missing data imputed using the last observation carried forward method. *p<0.0001; **p=0.0035 versus laser.
†BCVA data not available for 2/92 randomised patients. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks;
BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study.
Time (weeks)
Mean
change
from
baseline
in
BCVA
(ETDRS
letters)
Mean change in BCVA (secondary outcome)
Aflibercept 2q4
(n = 91)
Laser
(n = 90†)
Aflibercept 2q8
(n = 91)
Laser + rescue
aflibercept (n = 90†)

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VIBRANT: Early treatment is important to maximise
outcomes in patients with BRVO1,2
†BCVA data not available for 2/92 randomised patients. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BCVA = best-corrected
visual acuity; BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study.
Aflibercept 2q4
(n = 91)
Laser
(n = 90†)
Aflibercept 2q8
(n = 91)
Laser + rescue
aflibercept (n = 90†)
Time (weeks)
Mean
change
from
baseline
in
BCVA
(ETDRS
letters)
Mean change in BCVA (secondary outcome)

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VIBRANT: More patients gained vision and fewer
lost vision with aflibercept vs laser at week 241
Full analysis set. Missing data imputed using the last observation carried forward method.
*p<0.05 versus laser; †BCVA data not available for 2/92 randomised patients.
2q4 = 2 mg every 4 weeks; BCVA = best-corrected visual acuity.
Any vision gain ≥10 letters ≥15 letters ≥30 letters
Any vision loss
Proportion
of
patients
(%)
Aflibercept 2q4 (n = 91)
Laser (n = 90)†
Proportion of patients gaining/losing vision
(secondary outcome)
*
*
*
*
*

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VIBRANT: CRT reductions were rapid and sustained
over 52 weeks in eyes treated with aflibercept1,2
2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks;
BCVA = best-corrected visual acuity; CRT = central retinal thickness.
Time (weeks)
Mean
change
from
baseline
in
CRT
(μm)
Mean change in CRT (secondary outcome)
Aflibercept 2q4
(n = 91)
Laser
(n = 90)
Aflibercept 2q8
(n = 91)
Laser + rescue
aflibercept (n = 90)

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VIBRANT: NEI VFQ-25 near and distance activities
were improved with aflibercept versus laser
*p=0.003, **p=0.0047, †p=0.0061 versus laser. NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire.
Aflibercept 2q4 (n = 91)
Laser (n = 90)
*
**
Mean
change
from
baseline
in
subscale
score
on
the
NEI
VFQ-25
Questionnaire
†
Week 241 Week 522
Near
activities
Distance
activities
Visual
dependency
Near
activities
Distance
activities
Visual
dependency
Mean change in NEI VFQ-25 subscale scores
(secondary outcome)

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VIBRANT: Aflibercept increased the proportion
of eyes with retinal capillary perfusion at week 241
*p=0.0497 versus laser at week 24. 2q4 = 2 mg every 4 weeks.
• At 52 weeks, after rescue treatment in the laser arm, the perfusion
status was similar in the two arms2
Relative
difference
Proportion of perfused eyes (pre-specified exploratory outcome)
Proportion
of
perfused
eyes
(%)
Laser
(n = 90)
Aflibercept 2q4
(n = 91)
Baseline
Baseline
Week
24
Week
24

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VIBRANT: Aflibercept increased the proportion
of eyes without intraretinal or subretinal fluid1
Absolute
difference
Absolute
difference
*p=0.0303 aflibercept versus laser. †Majority of patients in the laser group received aflibercept rescue treatment from week 24.
1. Clark WL, et al. Ophthalmology. 2016;123:330–336.
Proportion of “dry” eyes (ad hoc exploratory outcome)
Proportion
of
dry
eyes
(%)
Laser + rescue aflibercept (n = 90)†
Baseline Week
24
Week
52
Aflibercept (n = 91)
Baseline Week
24
Week
52

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VIBRANT: Incidence of adverse events from baseline
to weeks 24 and 52 was similar for aflibercept vs laser
Safety analysis set. *Antiplatelet Trialists' Collaboration (APTC)-defined arterial thromboembolic events (ATEs)
include non-fatal stroke, non-fatal myocardial infarction, and vascular death as adjudicated by a masked committee.
AE = adverse event.
24 weeks1 52 weeks2
Laser
(n = 92)
Aflibercept
(n = 91)
Laser + rescue
aflibercept
(n = 92)
Aflibercept
(n = 91)
Ocular AEs (study eye), n (%) 25 (27.2) 34 (37.4) 44 (47.8) 45 (49.5)
Conjunctival haemorrhage 4 (4.3) 18 (19.8) 14 (15.2) 22 (24.2)
Retinal neovascularisation 3 (3.3) 0 4 (4.3) 0
Serious ocular AEs, n (%) 0 1 (1.1) 0 1 (1.1)
Non-ocular AEs, n (%) 46 (50.0) 43 (47.3) 63 (68.5) 61 (67.0)
Hypertension 10 (10.9) 6 (6.6) 15 (16.3) 10 (11.0)
Nasopharyngitis 5 (5.4) 6 (6.6) 8 (8.7) 8 (8.8)
Non-ocular serious AEs, n (%) 9 (9.8) 8 (8.8) 10 (10.9) 13 (14.3)
APTC-defined ATEs*, n (%) 1 (1.1) 0 2 (2.2) 0
Death, n (%) 1 (1.1) 0 1 (1.1) 0

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VIBRANT: Summary
• The first Phase III trial to compare an anti-VEGF agent with the prior
standard of care (macular grid laser photocoagulation therapy) in BRVO
• Patients were randomised to aflibercept 2q4 or laser
– At week 24, patients in the aflibercept group were switched to 2q8 regimen
• A significantly higher proportion of patients taking aflibercept gained ≥15
ETDRS letters from baseline at week 24 (primary outcome) and at week 52,
when compared with patients receiving laser therapy
• Mean CRT reductions from baseline to week 24 and week 52 were
significantly greater in the aflibercept arm vs laser arm
• Aflibercept is well tolerated in the treatment of visual impairment due to
macular oedema secondary to BRVO

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Posology of aflibercept for RVO (BRVO or CRVO)1
BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion.
1. EYLEA SmPC.
• After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than
one month.
• If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should
be discontinued.
• Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity.
Three or more consecutive, monthly injections may be needed.
• Treatment may then be continued with a treat-and-extend regimen with gradually increased treatment intervals to
maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of
these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened
accordingly.
• The monitoring and treatment schedule should be determined by the treating physician based on the individual
patient’s response.
• Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g.
optical coherence tomography or fluorescein angiography).
Consecutive monthly dosing until
disease stability (≥3 injections)
Treat and extend
Injection
visits
Monitoring
visits

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Management of macular oedema: Summary
DEX = dexamethasone.
• The efficacy of macular grid laser photocoagulation for the treatment of
macular oedema secondary to BRVO was demonstrated in BVOS
– Mechanism is not fully understood
• Intravitreal corticosteroids downregulate cytokine expression to inhibit
vascular permeability
– Triamcinolone demonstrated similar benefits to grid laser, but was
associated with higher rates of adverse events
– DEX demonstrated short-term improvements in BCVA, but repeat
dosing increased cataract formation
• Intravitreal anti-VEGF therapies block the actions of VEGF to alleviate
symptoms of BRVO
– Both ranibizumab and aflibercept are effective for the treatment of visual
impairment caused by macular oedema secondary to BRVO

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Management of other complications
• Neovascularisation
• Vitreous haemorrhage

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Sector pan-retinal photocoagulation

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Sector pan-retinal photocoagulation for BRVO
BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VEGF = vascular endothelial growth factor.
Arch Ophthalmol. 1986;104:34–41; 3. Stefansson E. Eur Ophthal Rev. 2009;2:76–79; 4. Dowler J. J R Soc Med.
2003;96:277–279.
Schematic diagram
showing change in
retina (A) before and
(B) after scatter laser
photocoagulation.
Destruction of
pigment epithelium
and photoreceptors
occurs
• Neovascularisation secondary to BRVO
• Reduces risk of vitreous haemorrhage
• Standard of care for peripheral retinal
ischaemia based on Branch Vein Occlusion
Study1,2
What it treats
• Reduces oxygen demand by destroying
photoreceptors within the retina3
• Hypoxia is corrected and production of
cytokines is normalised3
Mechanism
A B
Inner eye
Outer eye
Photoreceptors
Pigment epithelium
• Laser is directed at quadrant of ischaemia
• Avoid areas of intraretinal haemorrhage1
Technique
• Scarring4
• Loss of central vision4
Side effects

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BVOS outcomes led to laser photocoagulation
becoming standard of care for BRVO
BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study.
1. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41.
• Scatter laser photocoagulation in patients with BRVO:1
– Prevented development of neovascularisation
– Prevented vitreous haemorrhage in patients with
neovascularisation

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Vitrectomy

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Vitrectomy for BRVO
1. Buddi R, et al. Available here: http://www.reviewofophthalmology.com/content/d/wills_resident_case_series/
d/1213/p/22849/c/25432/. Accessed February 17, 2015.
• Vitrectomy is only necessary in situations where secondary
complications are present
Pars plana vitrectomy. Figure shows use of a
cutting instrument to remove vitreous humor
• Vitreous haemorrhage
• Tractional retinal detachment
(macular involvement)
• Epiretinal membrane
What it treats1 Light
source
Vitrector
Vitreous humor
Bleeding
Retina

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Management of other complications: Summary
• Scatter laser photocoagulation is used to treat
neovascularisation secondary to BRVO, and to
reduce the risk of vitreous haemorrhage
• Vitrectomy is only necessary in situations where secondary
complications are present
– Treats vitreous haemorrhage, tractional retinal detachment,
and epiretinal membrane secondary to BRVO

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RCO guidelines for the management of patients
presenting with BRVO
BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography; VA = visual acuity;
VEGF = vascular endothelial growth factor.
Measure VA
VA is better than 20/40
Macular oedema and
haemorrhages are NOT
masking the macula
Regularly observe
progress for
3 months
yes
no
no
Measure level
of ischaemia on
FFA
Mild to moderate
None
Severe
Consider treatment with
anti-VEGF therapy or
dexamethasone
No treatment.
Regularly observe for
neovascularisation
Anti-VEGF therapy
or dexamethasone
for three months
After 3 months
yes

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Local patient pathway
• [Placeholder – please insert information as needed]

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NICE guidelines for the management of patients
with BRVO
• Intravitreal dexamethasone implant:
https://www.nice.org.uk/Guidance/TA229
• Ranibizumab:
https://www.nice.org.uk/guidance/ta283
• Aflibercept:
https://www.nice.org.uk/guidance/indevelopment/gid-
ta10004

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Back-up slides

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Several growth and inflammatory factors are
associated with macular oedema in BRVO1
BRVO = branch retinal vein occlusion; IL = interleukin; MCP = monocyte chemotactic protein; PDGF = platelet-derived growth
factor; PlGF = placental growth factor; sICAM-1 = soluble intercellular adhesion molecule 1; sVEGFR-1 = soluble vascular
endothelial growth factor (VEGF) receptor 1; sVEGFR-2 = soluble vascular endothelial growth factor (VEGF) receptor 2.
1. Noma H, et al. Invest Ophthalmol Vis Sci. 2014;55:3878–3885.
Factor
Median value Relative
difference
P value
Control group BRVO group
sVEGFR-1, pg/mL 790 2433 3.08 <0.001
sVEGFR-2, pg/mL 85.5 537 6.28 <0.001
VEGF, pg/mL 22.5 83.5 3.71 0.033
PlGF, pg/mL 0.37 1.69 4.57 0.004
PDGF-AA, pg/mL 15.1 30.3 2.01 <0.001
sICAM-1, ng/mL 0.06 0.29 4.83 0.002
MCP-1, pg/mL 839 1721 2.05 <0.001
IL-6, pg/mL 2.73 8.17 2.99 0.013
IL-8, pg/mL 2.54 21.0 8.27 <0.001
IL-12, pg/mL 0.14 2.48 17.71 0.001
IL-13, pg/mL 0.63 4.09 6.49 0.025

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HORIZON: Ranibizumab maintained CFT
improvements achieved in BRVO
treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Due to early termination of the study, HORIZON
efficacy analyses (secondary outcomes) were presented for 24 rather than 36 months. CFT = central foveal thickness.
Mean
change
in
CFT
from
BRAVO
baseline
(μm)
Mean no. injections at month 24 2.1 2.4 2.0
Patients receiving rescue laser, n (%) 5 (7) 4 (6) 3 (5)
BRAVO baseline 12 15 18 21 24*
Time (months)
BRAVO HORIZON
Mean change in CFT
(secondary outcome)
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg/0.5 mg
Sham/0.5 mg ranibizumab
n = 104 (0.5 mg)
n = 103 (0.3 mg)
n = 96 (sham)
n = 63 (sham/0.5 mg)
n = 65 (0.3 mg/0.5 mg)
n = 72 (0.5 mg)

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RETAIN: Improvements in CFT in BRAVO
were maintained for patients enrolled in RETAIN
Dark grey line represents a value of 172 mm, the mean CFT reported in normal patients. Blue arrows indicate time of
assessment of primary outcomes (RETAIN: mean improvement in BCVA and patients [%] with oedema resolution).
BRVO = branch retinal vein occlusion; CFT = central foveal thickness.
• 50% of BRVO patients in RETAIN had resolution of macular oedema
• Those without resolution had three injections during the last year of follow-up
Mean change in CFT (secondary outcome)

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Anti-VEGF therapy and ischaemia1
1. Clark WL, et al. Ophthalmology. 2016;123:330–336.
• VIBRANT is the first phase III anti-VEGF clinical trial to include
ischaemic BRVO patients
– Defined as ≥10 disc areas of retinal capillary non-perfusion
– Aflibercept may be effective at reducing retinal ischaemia
 Further investigation is needed
Laser/rescue
aflibercept
Aflibercept
Week 24, % 17.6 29.0
Week 52, % 29.6 34.7
Proportion of eyes with a decrease in retinal ischaemia from baseline

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BVOS study design1,2
BVOS = Branch Vein Occlusion Study.
Scatter laser photocoagulation
Control
Group I
N = 319
Group II
N = 82
Group III
N = 139
Scatter laser photocoagulation
Control
Control

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BVOS: Inclusion criteria1,2
BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VA = visual acuity.
Group I Group II Group III
• BRVO occurring 3–18
months earlier
• An area of 5 disc diameters
of retinal involvement
• Sufficient clearing of
intraretinal haemorrhage
to permit safe laser
photocoagulation
• No diabetic retinopathy
• Absence of other ocular
disease-threatening VA
months earlier
• Disc and/or peripheral
neovascularisation
documented by stereo colour
fundus photography, and
photocoagulation
• No diabetic retinopathy
months earlier
• Macular oedema reducing VA
to 20/40 or worse
• Fluorescein angiographic
evidence of macular oedema
involving the fovea
photocoagulation
• Absence of haemorrhage
in the fovea

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Sheathotomy during vitrectomy for BRVO
1. Osterloh MD, Charles S. Arch Ophthalmol. 1988;106:1469–1471; 2. Kumagai K, et al. Retina. 2007;27:49–54;
3. Charbonnel J, et al. Graefes Arch Clin Exp Ophthalmol. 2004;242:223–228.
• High-risk procedure that may not provide additional benefits1–3
Arteriovenous adventitial sheathotomy.
A sharp tool is used to separate the common
adventitial sheath of the artery and vein
Only treatment available that treats
the cause of the occlusion1
What it treats
Separates common sheath connecting
artery and vein at arteriovenous
crossing1
Mechanism

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Prescribing information (1)
Eylea® 40 mg/ml solution for injection in a vial (aflibercept)
Prescribing Information
(Refer to full Summary of Product Characteristics (SmPC) before prescribing)
Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains
100 microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment of neovascular
(wet) age-related macular degeneration (AMD), macular oedema secondary to retinal
vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular
oedema (DMO) in adults and visual impairment due to myopic choroidal
neovascularisation (myopic CNV). Posology & method of administration: For
intravitreal injection only. Must be administered according to medical standards and
applicable guidelines by a qualified physician experienced in administering intravitreal
injections. Each vial should only be used for the treatment of a single eye. The vial
contains more than the recommended dose of 2 mg. The extractable volume of the vial
(100 microlitres) is not to be used in total. The excess volume should be expelled
before injecting. Refer to SmPC for full details. Adults: The recommended dose is 2
mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one
injection per month for three consecutive doses, followed by one injection every two
months. No requirement for monitoring between injections. After the first 12 months of
treatment, and based on visual and/or anatomic outcomes, the treatment interval may
be extended such as with a treat-and-extend dosing regimen, where the treatment
intervals are gradually increased to maintain stable visual and/or anatomic outcomes;
however there are insufficient data to conclude on the length of these intervals. If visual
and/or anatomic outcomes deteriorate, the treatment interval should be shortened
accordingly. The schedule for monitoring should therefore be determined by treating
physician and may be more frequent than the schedule of injections. For RVO (branch
RVO or central RVO), after the initial injection, treatment is given monthly at intervals
not shorter than one month. Discontinue if visual and anatomic outcomes indicate that
the patient is not benefiting from continued treatment. Treat monthly until maximum
visual acuity and/or no signs of disease activity. Three or more consecutive, monthly
injections may be needed. Treatment may then be continued with a treat and extend
regimen with gradually increased treatment intervals to maintain stable visual and/or
anatomic outcomes, however there are insufficient data to conclude on the length of
these intervals. Shorten treatment intervals if visual and/or anatomic outcomes
deteriorate. The monitoring and treatment schedule should be determined by the
treating physician based on the individual patient’s response. For DMO, initiate
treatment with one injection/month for 5 consecutive doses, followed by one injection
every two months. No requirement for monitoring between injections. After the first 12
months of treatment, and based on visual and/or anatomic outcomes, the treatment
interval may be extended such as with a treat-and-extend dosing regimen, where the
treatment intervals are gradually increased to maintain stable visual and/or anatomic
outcomes; however there are insufficient data to conclude on the length of these
intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should
be shortened accordingly. The schedule for monitoring should therefore be determined
by the treating physician and may be more frequent than the schedule of injections. If
visual and anatomic outcomes indicate that the patient is not benefiting from continued
treatment, treatment should be discontinued. For myopic CNV, a single injection is to
be administered. Additional doses may be administered if visual and/or anatomic
outcomes indicate that the disease persists. Recurrences should be treated as a new
manifestation of the disease. The schedule for monitoring should be determined by the
treating physician. The interval between two doses should not be shorter than one
month. Hepatic and/or renal impairment: No specific studies have been conducted.
Available data do not suggest a need for a dose adjustment. Elderly population: No
special considerations are needed. Limited experience in those with DMO over 75
years old. Paediatric population: No data available. Contraindications:
Hypersensitivity to active substance or any excipient; active or suspected ocular or
periocular infection; active severe intraocular inflammation. Warnings & precautions:
As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection
technique essential. Patients should be monitored during the week following the
injection to permit early treatment if an infection occurs. Patients must report any
symptoms of endophthalmitis without delay. Increases in intraocular pressure have
been seen within 60 minutes of intravitreal injection; special precaution is needed in
patients with poorly controlled glaucoma (do not inject while the intraocular pressure is
≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of
optic nerve head and manage appropriately. There is a potential for immunogenicity as
with other therapeutic proteins; patients should report any signs or symptoms of
intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign
of hypersensitivity. Systemic adverse events including non-ocular haemorrhages and
arterial thromboembolic events have been reported following intravitreal injection of
VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been
systemically studied. No data is available on concomitant use of Eylea with other anti-
VEGF medicinal products (systemic or ocular). Caution in patients with risk factors for
development of retinal pigment epithelial tears including large and/or high pigment
epithelial retinal detachment. Withhold treatment in patients with: rhegmatogenous
retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume
treatment until the break is adequately repaired.

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Prescribing information (2)
Withhold treatment and do not resume before next scheduled treatment if there is:
decrease in best-corrected visual acuity of ≥30 letters compared with the last
assessment; central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total
lesion area. Do not treat in the 28 days prior to or following performed or planned
intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit
outweighs the potential risk to the foetus. Women of childbearing potential have to use
effective contraception during treatment and for at least 3 months after the last
intravitreal injection. Populations with limited data: There is limited experience of
treatment with Eylea in patients with ischaemic, chronic RVO. In patients presenting
with clinical signs of irreversible ischaemic visual function loss, aflibercept treatment is
not recommended. There is limited experience in DMO due to type I diabetes or in
diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.
Eylea has not been studied in patients with active systemic infections, concurrent eye
conditions such as retinal detachment or macular hole, or in diabetic patients with
uncontrolled hypertension. This lack of information should be considered when treating
such patients. In myopic CNV there is no experience with Eylea in the treatment of
non-Asian patients, patients who have previously undergone treatment for myopic
CNV, and patients with extrafoveal lesions. Interactions: No available data. Fertility,
pregnancy & lactation: Not recommended during pregnancy unless potential benefit
outweighs potential risk to the foetus. No data available in pregnant women. Studies in
animals have shown embryo-foetal toxicity. Women of childbearing potential have to
use effective contraception during treatment and for at least 3 months after the last
injection. Not recommended during breastfeeding. Excretion in human milk: unknown.
Male and female fertility impairment seen in animal studies with high systemic
exposure not expected after ocular administration with very low systemic exposure.
Effects on ability to drive and use machines: Possible temporary visual
disturbances. Patients should not drive or use machines if vision inadequate.
Undesirable effects: Very common: Visual acuity reduced, conjunctival haemorrhage
(phase III studies: increased incidence in patients receiving anti-thrombotic agents),
eye pain. Common: retinal pigment epithelial tear, detachment of the retinal pigment
epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or
subcapsular), corneal abrasion or erosion, increased intraocular pressure, blurred
vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation
in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate
keratitis, conjunctival or ocular hyperaemia. Serious: cf. CI/W&P - in addition:
blindness, endophthalmitis, cataract traumatic, transient increased intraocular
pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (during the
post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and
isolated cases of severe anaphylactic/anaphylactoid reactions), vitreous haemorrhage,
cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis,
iritis, iridocyclitis, anterior chamber flare, arterial thromboembolic events (ATEs) are
adverse events potentially related to systemic VEGF inhibition. There is a theoretical
risk of arterial thromboembolic events, including stroke and myocardial infarction,
following intravitreal use of VEGF inhibitors. Consult the SmPC in relation to other side
effects. Overdose: Monitor intraocular pressure and treat if required.
Incompatibilities: Do not mix with other medicinal products. Special Precautions for
Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be
kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category:
POM. Package Quantities & Basic NHS Costs: Single vial pack £816.00. MA
Number(s): EU/1/12/797/002. Further information available from: Bayer plc, Bayer
House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone:
01635 563000. Date of preparation: September 2016
Eylea® is a trademark of the Bayer Group
Adverse events should be reported. Reporting forms
and information can be found at
www.mhra.gov.uk/yellowcard. Adverse events should
also be reported to Bayer plc.
Tel.: 01635 563500, Fax.: 01635 563703,
Email: pvuk@bayer.com

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