BRVO TREATMENT WITH INJECTION AND LASER

1. Preferred treatment in the management of BRVO :
Intravitreal Ranibizumab

2. Agenda
1. Introduction to RVO
2. Pathophysiology
3. Literature review of AntiVEGF - Ranibizumab
4. Literature Review of other antiVEGF therapies and Steroids

3. Retinal vein occlusion
• A significant cause of visual
impairment1
• Reduced quality of life and
functional activities of daily
living2
• 16 million people affected in
one or both eyes worldwide3
RVO is the second most common retinal vascular disorder after diabetic retinopathy1
1.Shahid et al. Br J Ophthalmol. 2006; 90: 627-639 2. Knudtson et al. Arch Ophthalmol. 2005; 123: 807-814
3. Rogers et al. Ophthalmology 2010;117:313–9 4. Mitchell et al. Arch Ophthalmol. 1996; 114: 1243-1247
Years
Prevalence of RVO varies with age4
Prevalence
(%)
0
1
2
3
4
5
<60 60-69 70-79 >80

4. Pathogenesis of RVO1
Compression of the vein
• Retinal vein/artery crossover points are major sites of RVOs1
• Veins have weaker walls than, and usually lie beneath, arteries
• Hardening of artery walls may cause compression of the vessel underneath
• Blood flow restriction may result in a thrombus and thus occlusion
Changes in blood vessel walls
• The venous endothelium and intima media are altered in RVO2
• Endothelial swelling and trophic alteration of the vessel wall
• Clinical evidence supports endothelial dysfunction as a major promotor for
atherosclerosis and thrombosis3
Changes in haematological factors
• Changes in blood composition may affect blood viscosity and coagulation
hence blood flow e.g. anticoagulant proteins, platelet aggregation disorders
and high plasma viscosity
1. Rehak M, Wiedemann P. J Thromb Haemost. 2010;8:1886–94
2. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–31
3. Versari D et al. Diabetes Care 2009;32(Suppl 2):S314–21

5. Branched retinal vein occlusion
 BRVO occurs more often than CRVO with a prevalence ranging from 0.2-2.0%1
 BRVO usually occurs at sites where arterioles cross over veins2,3
• This leads to acute (but often temporary) onset of blurred vision, possibly with focal hemorrhages4
• Only the portion of the peripheral retina drained by the obstructed branch is affected4
 Can be either ischemic or non-ischemic5
 Complications: NVD/NVE (macular edema main cause of visual impairment)
• Occlusion in major branch
• Most commonly in
superotemporal arcade
• Retinal haemorrhages and
potentially cotton wool spots
Major BRVO3 Macular BRVO3
• Occlusion in small tributary
draining the macula
• Microvascular changes, small
collateral channels and
sectorial macular oedema
1.Laouri M, et al. Eye 2011;25:981-988; 2. Brand CS. Eye 2012;26:S1–16;
2.Parodi MB et al. Ophthalmologica 2009;223:298–305; Lattanzio R, et al. Ophthalmologica 2011;225:135–43;

6. Treatment options: RVO1-3
• Edema
• Ischemia
• Neovascularization
Address
causes of
vision
impairment
1. Shahid H, et al. Br J Ophthalmol. 2006;90:627–39
2. Ford JA, et al. BMJ Open 2014;4:e004120
3. Gerding H, et al. Br J Ophthalmol. 2015;99:297–304
Interventions CRVO BRVO
Macular edema secondary to RVO
Anti-VEGF therapies  
Steroids  
Grid pattern laser
photocoagulation
X 

7. Long term management in a high risk population:
RVO is associated with serious co-morbidities
1. Werther W, et al. Arch Ophthalmol. 2011;129:326–31; 2. Shahid H, et al. Br J Ophthalmol. 2006;90:627–39;
3. Hayreh SS, et al. Am J Ophthalmol. 2001;131:61–77; 4. Elman MJ, et al. Ophthalmology 1990;97:1543–48;
5. Wong TY, et al. Ophthalmology 2005;112:540–7; 6. Cheung N, et al. Invest Ophthalmol Vis Sci. 2008;42:4297–302;
7. Chen HX, CleckJN. Nat Rev Clin Oncol. 2009:6;465–77
Renal disease6
Dyslipidemia6
Cardiovascular
disease2
Hypertension3-6
Diabetes3,4
Cerebrovascular
accident1
VEGF overexpression promotes
angiogenesis, as well as vascular
and endothelial cell integrity7
Systemic inhibition of VEGF may
lead to compromised wound
healing / tissue repair,
hypertension, arterial
thromboembolic events and
proteinuria7
The long-term safety profile of any treatment is a key consideration for physicians

8. AntiVEGF literature review - Ranibizumab
8
controlled trials have been performed in BRVO
1. Brown DM, et al. Ophthalmology 2010;117:1124-33; Heier JS, et al. Ophthalmology 2012;119:802-9;
2. Campochiaro PA, et al. Ophthalmology 2014;121:209-19; Campochiaro PA, et al. Ophthalmology 2014; 1212432-42;
3. Monés J, ESASO November 2014; Hattenbach L-O. World Ophthalmology Congress, Japan, 2014

9. RETAIN: Patients with CRVO and BRVO
maintainedtheir initial VA gains for 3.5 years
9
53.1% of the 32 CRVO patients enrolled in the RETAIN study gained
BCVA of 15 letters or more, and 43.8% of patients had a final BCVA of
20/40 or better.
32 patients with CRVO from the CRUISE study were enrolled in the RETAIN study.
Of the patients enrolled, 27 of 32 with CRVO completed 2 years of follow-up.
Campochiaro PA, et al. Ophthalmology 2014;121:209–19
13.9

10. SHORE supports flexible dosing of ranibizumab for both BRVO
and CRVO
10
Primary efficacy analysis: no significant difference in the slopes of the BCVA change from baseline from
Month 7 through Month 15 between treatment groups (P=0.509)
Data for all patients enrolled in the SHORE study (BRVO + CRVO)
*n=number of patients in each group at baseline; number of patients with observed BCVA changes
from baseline varies over time. Intent-to-treat observed data
Vertical bars are  1 SE of the mean Campochiaro PA, et al. Ophthalmology 2014;121:2432–42

11. SHORE: PRN dosing in patients & BCVA gain
11
Protocol-driven fixed monthly dosing
n=number of patients in each group at baseline; number of patients with observed BCVA changes
from baseline varies over time. Intent-to-treat observed data Campochiaro PA, et al. Ophthalmology 2014;121:2432–42
Protocol-driven fixed monthly dosing
CRVO patients BRVO patients

12. Long-term and head-to-head studies
BRIGHTER1
COMRADE-B2
BRVO
1. www.clinicaltrials.gov/ct2/show/NCT01599650
2. www.clinicaltrials.gov/ct2/show/NCT01396057

13. *Monthly ranibizumab treatment until study eye’s VA stabilization for three consecutive monthly assessments, followed by treatment on a PRN basis. †Laser treatment to be administered as soon as
indicated to patients with perfused macular edema, at minimal intervals of 4 months (105 ± 15 days); Laser treatment not to be administered if BCVA is ≥79 letters or
if no macular edema is present; from Month 6, patients can be treated with ranibizumab
Head to Head Study in BRVO

14. Demographics and
ocular characteristics
(Randomized set)
Ranibizumab
0.5 mg
(N = 183)
Ranibizumab
0.5 mg
+ adjunctive
laser
(N = 180)
Laser
(N = 92)
Laser with
Ranibizumab
0.5 mg from
Month 6
(N = 66)
Laser only
from
Month 6
(N = 26)
Age (years), mean (SD) 64.7 (10.3) 67.3 (10.4) 67.7 (9.7)* 67.9 (9.2) 67.1 (11.0)
VA, mean (SD), letters 59.5 (11.8) 56.6 (13.2) 56.5 (14.1) 56.8 (13.9) 55.6 (15.1)
Duration of BRVO (months)
Mean (SD) 10.3 (19.6) 9.3 (19.9) 10.5 (26.7) 13.8 (30.8) 2.2 (2.2)
Duration of BRVO – n (%)
≤12 months 145 (79.2) 145 (80.6) 76 (82.6) 51 (77.2) 25 (96.2)
≥12 months 36 (19.7) 33 (18.3) 14 (15.2) 14 (21.2) 0
Missing 2 (1.1) 1 (0.6) 2 ( 2.2) 1 (1.5) 1 (3.8)
#Missing data, n (%): 2 (1.1), 1 (0.6), and 1 (1.1) for ranibizumab, ranibizumab +laser and laser, respectively
BRIGHTER: A broader inclusion criteria to better
represent the BRVO patient population
Over 15% of patients had a disease duration of greater than 12 months

15. *P<0.0001, for both ranibizumab and ranibizumab with or without laser versus laser alone, pairwise ANOVA
Full set analysis; last observation carried forward.

16. Full set analysis; last observation carried forward.
Months

17. www.clinicaltrials.gov/ct2/show/NCT01396057

18. Full analysis set (last observation carried forward)
Error bars show standard deviations based on full analysis set/last observation carried forward.

19. Key take Aways
Considering BRVO AntiVEGF’s provide early and sustained VA gain
AntiVEGF + laser may provide additional and sustained VA gain
Safety and Efficacy of the anti VEGF molecule should be considered before hand
Steroids also helps to maintain and achieve VA gain
19

20. 6/12 hypertension with LE
BRVO
TREATMENT WITH
2 Ranibizumab Injection
monthly + scatter laser
Now 6/6