Review
Pharmacotherapy for treatment of retinal vein occlusion Valentina Sarao, Federica Bertoli, Daniele Veritti & Paolo Lanzetta† University of Udine, Department of Ophthalmology, Udine, Italy
Introduction
2.
Anti-VEGF therapy
3.
Steroids
4.
Promising strategies and new drugs
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitat de Girona on 01/19/15 For personal use only.
†
1.
5.
Conclusion
6.
Expert opinion
Introduction: Retinal vein occlusion (RVO) is a common vascular condition, which may cause blindness and impaired vision as a result of the development of macular oedema. The management of macular oedema due to RVO is complex and a multidisciplinary approach is required in order to limit disease progression and achieve a better clinical outcome. Areas covered: An update and a brief review on the current treatment strategies were provided in patients with macular oedema following RVOs. Evidence available from prospective, multicentre clinical studies evaluating the use of VEGF inhibitors and steroids and from a selective literature search is reported. Expert opinion: For many years, laser photocoagulation has been considered the standard of care for the treatment of branch RVO. However, new treatment modalities have been evaluated through randomised controlled trials. Recently, anti-VEGF agents and corticosteroids have been shown to be efficacious options in the treatment of RVO. Keywords: dexamethasone, laser, retinal vein occlusion, steroids, triamcinolone, VEGF. Expert Opin. Pharmacother. (2014) 15(16):2373-2384
1.
Introduction
Retinal vein occlusions (RVOs) are the second most common retinal vascular disease after diabetic retinopathy and can be divided into two primary categories depending on the site of obstruction: central RVO (CRVO) when the occlusion involves the whole central retinal vein, and branch RVO (BRVO) when the occlusion involves only one branch of the central retinal vein [1-3]. Population studies have estimated that there are about 520 cases of RVO per million population. These include 442 per million of BRVO and 80 per million of CRVO [4,5]. In the Beaver Dam Eye Study the 15-year cumulative incidence of CRVO and BRVO was 0.5 and 1.8%, respectively [6]. The pathogenesis of RVO is multifactorial and follows the principles of Virchow’s triad: stasis (generated by mechanical compression of the vein), damage to the vessel wall and hypercoagulability [1]. BRVO occurs at arterio-venous crossing sites that share a common adventitia [7]. CRVO is caused by external compression of the central retinal artery, which shares a common fibrous sleeve with the vein [8]. Thrombosis within a retinal vein leads to a partial obstruction of blood flow. The subsequent increased intraluminal pressure can lead to leakage of fluids and proteins across the vascular wall into the surrounding retinal tissue, resulting in local oedema. The increased interstitial oncotic pressure perpetuates tissue oedema, which impedes capillary perfusion and leads to ischemia. The stagnation of blood in the capillary induces hypoxia, which in turn causes damage to capillary endothelium that contributes to leakage of blood into the extracellular space. Furthermore, endothelial damage may result in a mild chronic inflammation of the affected vessels, with release of inflammatory mediators such as prostaglandins, leukotrienes, intercellular adhesion molecule 1 (ICAM-1), integrins TNF-a and VEGF. These cytokines weaken the blood--retinal barrier and help to perpetuate the oedema. 10.1517/14656566.2014.956083 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . .
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Retinal vein occlusion (RVO) is a common vascular condition that may cause blindness and impaired vision. The management of macular oedema due to RVO is complex and a multidisciplinary approach is required in order to limit disease progression and achieve a better clinical outcome. Anti-VEGF agents may provide an improvement in visual acuity by two to four lines, and this outcome can be maintained over time (BRAVO, CRUISE, HORIZON, RETAIN, COPERNICUS, GALILEO). Steroids are effective in reducing central macular thickness and improving visual acuity, even if different side effects have been reported. (SCORE, GENEVA). The duration of macular oedema is a crucial factor influencing visual acuity gain after treatment: patients with lower duration of macular oedema showed the better functional results. Several clinical trials are being conducted to evaluate additional novel agents to treat macular oedema following RVO.
This box summarises key points contained in the article.
VEGF, in particular, has an important role in the disease. It is produced by retinal pigmented epithelial cells, endothelial cells, Mu¨ller cells and other ocular tissues in response to retinal hypoxia and binds to specific receptors on endothelial cells acting as a pro-angiogenetic and permeabilisating factor. Even if the primary venous obstruction is overcome via the formation of new collateral vessels, the macular oedema can persist for much longer due to a self-perpetuating cycle of VEGFinduced vascular permeability, which leads to macular oedema, capillary damage, and retinal ischemia, stimulating further release of VEGF and other inflammatory cytokines and causing chronic macular oedema. These cytokines constitute possible targets for new therapeutic strategies [9-12]. The main cause of visual loss in RVO is macular oedema [9]. In BRVO 50 -- 60% of eyes have a final visual acuity ‡ 5/10, even without treatment. In CRVO, usually visual acuity is poor at onset and declines further over time. Up to 34% of non-ischemic CRVO convert to ischemic forms within 3 years. Retinal neovascularisation may occur in 20% of non-perfused CRVO and 60% of those will develop neovascular glaucoma [1]. Visual acuity before treatment is an important prognostic factor. In particular, for eyes with an initial visual acuity ‡ 2.5/10 the prognosis is good even without treatment. Eyes with initial visual acuity £ 1/10 have a significantly worse prognosis compared to previous [1]. Macular grid laser photocoagulation represented the standard of care in patients with chronic macular oedema secondary to BRVO and visual acuity between 1/10 and 5/10 and if chosen it should be performed by 3 -- 6 months after the initial event and after resorption of most of the haemorrhages [13]. The Branch Vein Occlusion Study Group [13] remains today the largest international multicentre study that has demonstrated the effectiveness of grid photocoagulation 2374
in reducing macular oedema and improving visual acuity in patients with BRVO [9]. Macular laser photocoagulation is not recommended for the treatment of macular oedema in CRVO because it does not guarantee a significant improvement in visual acuity [14]. Panretinal photocoagulation of the ischemic retina is indicated both in BRVO and in CRVO if iris, retinal or disc neovascularisations are present. This treatment should be performed promptly to prevent the risk of neovascular glaucoma and vitreous haemorrhage [9,15]. 2.
Anti-VEGF therapy
RVO leads to an increased expression of VEGF by retinal pigment epithelium cells, causing neovascularisation and vascular hyperpermeability with subsequent breakdown of the blood--retina barrier and macular oedema [16]. The introduction of VEGF inhibitors is considered as the beginning of a new era in the treatment of macular oedema secondary to RVO targeting the disease at the causal molecular level. All three currently available anti-VEGF agents (ranibizumab, aflibercept, bevacizumab) have been applied successfully in reducing macular oedema due to RVO. A description of drugs that positively completed Phase III clinical trials are detailed in Tables 1 and 2. A short description is given below, and readers are referred to other studies for more details. Ranibizumab Ranibizumab (Lucentis; Genentech, Inc., San Francisco, CA, and Novartis AG, Basel, Switzerland) is a fragment of a recombinant, humanised, monoclonal antibody (48 kDa) that binds to and inhibits all the biologically active forms of VEGF-A [17,18]. Two randomised, double-masked, multicentre Phase III trials, the CRUISE and BRAVO studies, comparing monthly intravitreal injections of 0.3 or 0.5 mg ranibizumab with sham injections in patients with macular oedema following CRVO and BRVO [19-23]. The 6-month preliminary results showed in both studies a significant improvement in visual acuity in the treated groups versus the control groups with low rates of adverse side effects. This led to the FDA and EMA (European Medicines Agency) approval of ranibizumab 0.5 mg for the treatment of macular oedema secondary to BRVO and CRVO. In an open-label, single-arm, multicentre extension trial, the HORIZON study, patients who completed the CRUISE and BRAVO trials were evaluated at least every 3 months and treated with ranibizumab injections given as needed. Data were available for 181 patients at 12 months. Among patients with CRVO, visual acuity decreased by 4.2, 5.2 and 4.1 letters in the sham/0.5, 0.3/0.5 and 0.5 mg treatment groups, respectively, at the end of HORIZON trial. The mean number of ranibizumab injections was 2.9, 3.8 and 3.5, respectively. These data showed that the reduced frequency of ranibizumab injections in the second year was observed in 2.1
Expert Opin. Pharmacother. (2014) 15(16)
Expert Opin. Pharmacother. (2014) 15(16)
92
68
104
30
63.8 13.3 67.4 12.4 67.5 2.0 69.2 12.8
±
±
±
±
59.9 ± 12.4
70.4 ± 10.4
70.6 ± 12.6
65.4 ± 13.1
130
30
67.6 ± 12.4
69.7 ± 11.6
67.5
65.5
Age (years ± SD)
130
132
73
114
Eyes (N)
88
12 months
12 months
12 months
12 months
12 months
Follow-up
Observation
CRVO
CRVO
CRVO
CRVO
CRVO
Disease
91
4-monthly PRN
6-weekly, then 6-weekly bevacizumab Monthly for 6 months, then IAI PRN
Monthly for 6 months, then IAI PRN Monthly for 6 months, then IAI PRN Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN 6-weekly
Regimen
TA 4 mg
TA 1 mg
Sham
Bevacizumab 1.25 mg/ Bevacizumab Sham/ Bevacizumab 1.25 IAI 2 mg
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg
Sham/IAI 2 mg
IAI 2 mg
Exposure
4
2.9
2.6
3
2.9
3.3
3.6
1.8
2.7
67.0
71.4
78.3
10.3
6.8
11.7
2
0
0
16.4
14.9
Capillary nonperfusion (%)
50.9 15.4 50.6 14.9 51.0 14.4 52.1 13.1
±
±
±
±
53.8 ± 15.6
43.9± 16.0
44.4 ± 15.3
49.2 ± 14.7
48.1 ± 14.6
47.4 ± 14.8
48.9 ± 14.4
50.7 ± 13.9
Mean BCVA (letters ± SD)
Baseline characteristics Duration ME (months)
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; CRT: Central retinal thickness; TA: Triamcinolone acetonide.
[43]
SCORE
[34]
GALILEO
Epstein et al.[38]
[21]
CRUISE
[31]
COPERNICUS
Study
Table 1. Summary of randomised clinical trials in retinal vein occlusions.
40
42
43
17.6
16.5
33.3
30
20
23
25
24.6
24.7
BCVA < 35 letters (%)
638 224 643 266 641 248 695 208
±
±
±
±
683 ± 234
729 ± 195
712 ± 330
687 ± 237
688 ± 253
679 ± 242
672 ± 245
661 ± 237
Mean CRT (mm ± SD)
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-12.1
-1.2
-1.2
+ 3.8
+ 16.9
+ 4.6
+ 16
+ 7.3
+ 13.9
+ 13.9
+ 3.8
+ 16.2
Mean BCVA change (letters ± SD)
6.8
25.6
26.5
32.4
60.2
33.3
60
33.1
50.8
47
30.1
55.3
0
2.0
2.2
10.5 ± 4.2
11.8 ± 2.8
9
9
3.7
3.3
3.8
3.2 ± 0.3
2.7 ± 0.2
Number of injections (mean ± SD)
Final outcomes BCVA gain > 15 letters (%)
-277
-261
-196
-219
-423
-404
-435
-427
-462
-452
-381
-413
Mean CRT change (mm ± SD)
Pharmacotherapy for treatment of retinal vein occlusion
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12 months
136
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg 67.5 ± 11.8 65.2 ± 12.7
132
±
±
±
±
131
134
67.2 12.4 68.1 10.6 67.4 11.2 66.6 11.2
63.9
426
137 BRVO
12 months
64.7
64.9
Age (years ± SD)
427
414
Eyes (N)
Grid Laser
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN
BRVO
12 months
Follow-up
3.7
3.3
3.6
4.5
4.6
4.1
5.2
5.2
5.1
Duration ME (months)
0
0
0
70.1
73.9
69.8
n/a
n/a
n/a
Capillary nonperfusion (%)
±
±
±
±
57.4 ± 12.2
53.0 ± 12.5
58.2 11.3 56.1 13.4 56.8 13.0 56.0 12.1
53.9 ± 10.4 54.3 ± 9.9 54.8 ± 9.9
Mean BCVA (letters ± SD)
Baseline characteristics
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; CRT: Central retinal thickness; TA: Triamcinolone acetonide.
[22]
BRAVO
[44]
RVO
Disease
138
TA 1 mg
SCORE
6-monthly PRN, then dexamethasone 0.7 mg 4-monthly PRN
6-monthly PRN
Regimen
TA 4 mg
Dexamethasone 0.35 mg Dexamethasone 0.7 mg Sham
GENEVA
[46]
Exposure
Study
Table 1. Summary of randomised clinical trials in retinal vein occlusions (continued).
6.8
9.9
6.7
24
25
20
n/a
n/a
n/a
BCVA < 35 letters (%)
±
±
±
±
488 ± 192
551 ± 223
521 198 516 160 537 198 522 201
555 ± 204 562 ± 188 539 ± 186
Mean CRT (mm ± SD)
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+ 12.1
+ 18.3
+ 16.4
+ 4.2
+ 4.0
+ 5.7
+4
+6
n/a
Mean BCVA change (letters ± SD)
43.9
60.3
56.0
28.9
27.2
25.6
21
24
n/a
BCVA gain > 15 letters (%)
9.1
8.4
8.5
0
2.1
2.2
1
2
n/a
Number of injections (mean ± SD)
Final outcomes
-273
-347
-313
-224
-170
-149
-267
-263
-263
Mean CRT change (mm ± SD)
V. Sarao et al.
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Expert Opin. Pharmacother. (2014) 15(16)
Observation
TA 4 mg
TA 1 mg
Sham
4-monthly PRN
CRVO
88
91
92
68
Weeks 0 -- 24 Weeks 24 -- 52 Weeks 0 -- 24 Weeks 24 -- 52 Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
104
5.8%
14.4%
8.6%
n/a
3.5% 3.5% 5% 26% (‡ 35 mmHg) 8% 33% (‡ 35 mmHg) 1% 18% (‡ 35 mmHg)
5.9%
13.4%
8.7%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
1.8%
n/a
0%
0%
0%
7.0%
0%
n/a
1.7% 3.8%
n/a
n/a
0.9% 0%
n/a
4%
0%
4%
1.8%
1.5%%
1%
0%
n/a
n/a
1.8%
7%
5.4%
5.3%
3.3%
8.1%
0.9%
1.8%
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
0%
0%
0%
0%
0%
0%
0%
0.9%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
0%
0%
0%
0%
1%
0%
0%
0%
0%
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
1.8%
0%
1.6%
0%
1.7%
1.4%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
1.8%
3.9%
1.6%
2.3%
0%
0%
0%
0.9%
2%
4%
9%
0%
0%
0%
1%
0%
0%
1.8%
7.0%
3.9%
1.5%
3.3%
8.1%
0%
0%
Iris Lens Vitreous Endophth- Pseudo- Rhegmato- Retinal Any tear intraocular neovascuDamage haemorrhage almitis endophthgenous almitis retinal inflammation larisation event detachment
0%
Cataract
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; IOP: Intraocular pressure; TA: Triamcinolone acetonide.
[43]
SCORE
[34]
Weeks 0 -- 48
30
6-weekly, then 6-weekly bevacizumab CRVO Monthly for 6 months, then IAI PRN
n/a
Weeks 3.88% 0 -- 24 Weeks 24 -- 52
130
Weeks 0 -- 48
Weeks 0 -- 52
8.5%
Weeks 12.3% 0 -- 24 Weeks 24 -- 52 Weeks 13.5% 0 -- 24 Weeks 24 -- 52 Weeks 8.3% 0 -- 52
Increased IOP
130
132
73
114
30
CRVO
CRVO
Disease Eyes Study (N) period
CRVO
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN 6-weekly
Monthly for 6 months, then IAI PRN
Sham/IAI 2 mg
Ranibizumab 0.3 mg
Monthly for 6 months, then IAI PRN
Regimen
IAI 2 mg
Exposure
Epstein Bevacizumab et al. [38] 1.25 mg/ Bevacizumab Sham/ Bevacizumab 1.25 GALILEO IAI 2 mg
[21]
CRUISE
[31]
COPERNICUS
Study
Table 2. Safety outcomes of randomised clinical trials in retinal vein occlusions.
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Pharmacotherapy for treatment of retinal vein occlusion
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2378
Exposure
Regimen
BRAVO
Expert Opin. Pharmacother. (2014) 15(16)
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN BRVO
BRVO
RVO
Cataract
Weeks 2.3% 0 -- 24 Weeks 24 -- 52
132
6.9%
2% (‡ 35 mmHg) 14% (‡ 35 mmHg) 1% (‡ 35 mmHg) 5.2%
2.6%
3.1%
6.2%
4.5%
13%
35%
25%
n/a 19.8% (‡ 10 mmHg) 15.4% 29.8% (‡ 10 mmHg) 12.6% 12.5% (‡ 10 mmHg)
Weeks 0 -- 52
Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
Increased IOP
131
134
137
138
136
426
427
414
Disease Eyes Study (N) period
0%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
0.9%
4.6%
1.5%
5.2%
0%
0.7%
0.74%
n/a
n/a
n/a
0%
0%
0.8%
0%
0%
0.7%
0%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
0%
0%
0.7%
0%
0.7%
1.5%
n/a
n/a
n/a
0%
0%
0%
0.7%
0%
0.7%
0%
n/a
n/a
n/a
0.9%
3.1%
0%
2.2%
n/a
n/a
n/a
n/a
n/a
n/a
0%
2.3%
0.8%
0.7%
0%
0.7%
0%
n/a
n/a
n/a
Lens Vitreous Endophth- Pseudo- Rhegmato- Retinal Any Iris tear intraocular neovascuDamage haemorrhage almitis endophthgenous almitis retinal inflammation larisation detachment event
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; IOP: Intraocular pressure; TA: Triamcinolone acetonide.
[22]
Grid Laser
GENEVA Dexamethasone 6-monthly 0.35 mg PRN [46] Dexamethasone 0.7 mg Sham 6-monthly PRN, then dexamethasone 0.7 mg TA 1 mg 4-monthly SCORE PRN TA 4 mg [44]
Study
Table 2. Safety outcomes of randomised clinical trials in retinal vein occlusions (continued).
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V. Sarao et al.
Pharmacotherapy for treatment of retinal vein occlusion
conjunction with worsening of outcome measures in CRVO patients. Many patients with CRVO who had substantial gains during 1 year of aggressive ranibizumab treatment may decline during a second year in which there is reduced frequency of injections and a less frequent monitoring visits [23,24]. Aflibercept Aflibercept (Eylea, previously known as VEGF-Trap Eye; Regeneron Pharmaceuticals, Tarrytown, NY, USA, and Bayer HealthCare, Berlin, Germany) is a novel anti-VEGF agent that recently gained FDA approval for the treatment of macular oedema due to CRVO. It is fully human recombinant fusion protein composed of the second Ig domain of VEGFR1 and the third Ig domain of VEGFR2, fused to the Fc region of human IgG1 [25]. Its binding affinity for VEGF is substantially greater than that of either bevacizumab or ranibizumab [26]. It could have a substantially longer duration of action in the eye [27], allowing for less frequent administration, as supported by early clinical trials [28-34]. Aflibercept was recently investigated in patients with macular oedema following BRVO. The VIBRANT trial was a double-masked, Phase III, randomised, active-controlled study of 183 patients with macular oedema secondary to BRVO [35]. Patients received randomly either 2 mg intravitreal aflibercept every 4 weeks or laser treatment, up to week 24. At week 24, 53% of treated eyes gained at least 15 letters of BCVA from baseline compared with 27% of laser-treated eyes (p < 0.001). The mean BCVA gain was of 17 letters in the treatment group at 24 weeks compared with 6.9 letters in the laser-treated group.
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2.2
Bevacizumab Bevacizumab (Avastin; Genentech, San Francisco, CA, USA, and Roche, Basel, Switzerland) is a full-length recombinant humanised monoclonal antibody against VEGF with 93% of its amino acid sequence derived from human IgG. Many uncontrolled case series have reported that intravitreal administration of bevacizumab can lead to a visual improvement and resolution of macular oedema following RVO [36,37]. However, because of the variation in dosing and treatment regimens among these studies, both long-term outcomes and safety data remain unclear [38]. Several short-term studies have reported the efficacy of bevacizumab in improving visual acuity and retinal thickness in patients with macular oedema following BRVO, even if the duration of action is often provisional and requires repeated injections [39]. Recently, a large case series have shown favourable 2-year results using bevacizumab to treat macular oedema due to BRVO. During the 2-year follow-up period, 105 patients received an intravitreal bevacizumab injection at baseline and then at physician’s discrection. At 24 months, the mean BCVA improved significantly by 0.3 LogMAR in 69% of 2.3
eyes (p = 0.001). The mean number of treatments at the end of the follow-up was 3.8 [40]. 3.
Steroids
The rationale for using corticosteroids for the treatment of macular oedema secondary to RVO is that these drugs have anti-inflammatory, anti-angiogenic, and anti-permeability properties. Steroids are thought to act by the induction of phospholipase A2, which reduces leukocyte chemotaxis and decreases levels of potent inflammatory cell mediators such as prostaglandins and leukotrienes. Corticosteroids have also been shown to reduce gene expression of pro-inflammatory mediators such as VEGF, TNF-a and other inflammatory chemokines, and induce the expression of anti-inflammatory factors such as pigment-derived growth factor. Additionally, they seem to reduce the expression of MMPs and to downregulate ICAM-1 on choroidal endothelial cells [41]. Triamcinolone acetonide Triamcinolone acetonide is a synthetic steroid of the glucocorticoid family. Data available in literature support its effectiveness in reducing macular oedema secondary to RVO [42]. The SCORE study (The Standard Care versus Corticosteroid for REtinal vein occlusion) consists of two multicentre, randomised, Phase III trials. The SCORE-CRVO study compared two different doses of intravitreal triamcinolone (1 and 4 mg) to the standard of care, represented by observation, in 271 eyes with CRVO. At 12 months, the proportion of patients who experienced a visual acuity gain of 15 letters or more was similar among the three groups (27% in the group treated with triamcinolone 1 mg, 26% in the group treated with the 4 mg dose and 7% in the control group). At month 24, however, a loss in visual acuity letter scores of 15 letters or more was noted in 48% of the observation group versus 31% of the triamcinolone 1 mg group and 26% of the triamcinolone 4 mg group. All three study groups showed similar optical coherence tomography (OCT)-measured centre point thickness decreases from baseline through follow-up with the exception of the month 4 visit. At 120 days, the percentage of participants with a centre point thickness inferior to 250 µm was greater in the 4 mg triamcinolone group and the median decrease in central retinal thickness was 196 µm in the 4 mg triamcinolone group, 77 µm in the 1 mg triamcinolone group and 125 µm in the observation groups (p < 001). In terms of safety, an increase in intraocular pressure (IOP) of at least 35 mmHg was noted in 5 and 8% of patients in the 1 and 4 mg triamcinolone doses, respectively, and in 1% of patients in the observation group. The percentage of eyes that initiated IOP-lowering medication through 12 months was 8% in the observation group, 20% in the 1 mg triamcinolone arm and 35% in the 4 mg triamcinolone group. Among eyes that were phakic at baseline, the estimate through month 12 of cataract formation or progression in the observation group was 18% compared with 26 and 33% for 3.1
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the 1 and 4 mg triamcinolone groups, respectively. While no eyes in the observation or 1 mg triamcinolone groups had cataract surgery through month 12, four eyes in the 4 mg group received cataract surgery. Similarly, cataract surgery was more frequent between months 12 and 24 in the 4 mg group, with 21 eyes receiving cataract surgery compared with 3 in the 1 mg group and 0 in the observation group [43]. The SCORE-BRVO study enrolled 411 patients with macular oedema secondary to BRVO and evaluated the efficacy of two different doses of intravitreal triamcinolone (1 and 4 mg) compared with grid laser photocoagulation. There was no significant difference in visual acuity among the three groups at 12 months. The percentage of eyes gaining > 3 Early Treatment Diabetic Retinopathy Study lines was 26, 27 and 29%, respectively. All three study groups showed OCT-measured centre point thickness decreases from baseline throughout follow-up. At the month 4 visit, the median decrease was 142 µm in the 4 mg triamcinolone group, 77 µm in the 1 mg group and 113 µm in the standard of care group. The follow-up instead showed that from month 12 to 36 mean improvement from baseline in visual acuity letter score was greater in the standard care group compared with the two triamcinolone groups (p < 0.05 at months 16, 20, 24 and 32, based on analysis of variance) and in the laser-treated group there was also a greater reduction of macular thickness. In terms of safety, at month 12, the rates of elevated IOP were similar for the observation and 1 mg groups, but higher in the 4 mg group: an increase in IOP of at least 35 mmHg was noted in 1, 2 and 14% of patients respectively. IOPlowering medication was initiated through 12 months in 41% of eyes in the 4 mg triamcinolone group, 7% of eyes in the 1 mg triamcinolone arm and 2% of eyes in the standard of care group. Among eyes that were phakic at baseline, incidence of cataract formation or progression through month 12 in the standard care group was 13% compared with 25 and 35% in the 1 and 4 mg triamcinolone arms, respectively. Through month 12, cataract surgery was reported for three participants in the standard of care group versus none in the 1 mg triamcinolone group and four in the 4 mg triamcinolone group. Cataract surgery was more frequent between months 12 and 24 in the 4 mg group, with 35 study eyes receiving such surgery, compared with 8 in the 1 mg study group and 6 in the standard of care group. The rates of cataract formation and IOP elevation, therefore, were higher in the steroid groups. Based on these data, the recommendation from the study was that laser remains the standard of care for BRVO [44]. Dexamethasone Dexamethasone intravitreal implant is a sustained-release formulation, which allows to achieve clinically effective concentrations of this drug directly into the vitreous. The use of a sustain-release implant is needed because dexamethasone, while having a 5 times greater anti-inflammatory potency than triamcinolone acetonide, shows a shorter intravitreal half-life. The 3.2
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GENEVA study (Global Evaluation of Implantable Dexamethasone in RVO with macular oedema) included two identical, multicentre, prospective, randomised, double-blind, 6-month, sham-controlled clinical trials. A total of 1267 patients with vision loss due to macular oedema associated with BRVO or CRVO were enrolled. In the 6-month initial treatment phase, patients were randomised to the administration of dexamethasone 700 µg (n = 427) or dexamethasone 350 µg (n = 414) or sham (n = 426). The proportion of patients that achieved an improvement in visual acuity of 15 or more letters was 22% in the 700 µg group, 23% in the 350 µg group and 13% in the sham group at month 3 (p < 0.001). These data were no longer statistically significant at month 6. Eyes receiving dexamethasone implant 0.7 or 0.35 mg achieved a 15-letter improvement in BCVA significantly faster than the eyes receiving sham treatment. The cumulative response rate for the time to reach a 15-letter improvement from baseline BCVA was 41% in the dexamethasone implant 0.7 mg group, 40% in the 0.35 mg group and 23% in the sham group (p < 0.001). The reduction in mean central retinal thickness was 208 ± 201 µm in the 700 µg group, 177 ± 197 µm in the 350 µg group and 85 ± 173 µm in the sham group at month 3 (p < 0.001) at day 180, but not statistically significant at month 6. In terms of safety, for both CRVO and BRVO patients, raised IOP peaked at month 2, but declined by month 3 and was close to 0% by month 6, with 19% of patients requiring an IOP-lowering agent and 0.7% of patients requiring a IOP-lowering surgical procedure. Similarly, rates of cataract progression were low, 7% progression at month 6 compared with 4% in the sham group [45]. In the extension open-label phase of the study, all eligible eyes received a 0.7-mg dexamethasone implant and were followed-up for additional 6 months. Retreatment criteria were: BCVA < 84 letters or retinal thickness of > 250 µm in the central subfield. The percentage of patients initially treated with dexamethasone 0.7 mg who required only a single treatment in 12 months of follow-up was 19%. The group that received a 0.7-mg dexamethasone implant during the first 6 months and a second 0.7 mg implant at day 180 had a 32% improvement in BCVA from baseline. Up to 27% of patients who were in the sham group during the first 6 months and were given their first 0.7 mg dexamethasone implant at day 180 had at least a 15-letter improvement in BCVA from baseline at visits during the open-label phase of the study. At 90 days after open-label treatment with dexamethasone implant 0.7 mg, the mean reduction in retinal thickness from baseline was 263 ± 219 µm in the retreated dexamethasone 0.35/0.7 mg group, 263 ± 217 µm in the retreated 0.7/0.7 mg dexamethasone group and 267 ± 206 µm in patients who received their first injection of dexamethasone implant. Over 12 months, cataract progression was found in 29.8% of phakic eyes that received two implants of 0.7 mg versus 5.7% of sham-treated phakic eyes; cataract surgery was performed in 1.3% of phakic eyes that received two implants of
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Pharmacotherapy for treatment of retinal vein occlusion
0.7 mg and in 1.1% of sham-treated phakic eyes. In eyes that received two of the 0.7 mg implants, an increase in IOP of at least 10 mmHg was seen in 12.6% of eyes after the first treatment and 15.4% of eyes after the second treatment [46]. Based on the GENEVA study results, intravitreal dexamethasone implant (Ozurdex) has become the first drug approved by the FDA and EMA for the treatment of macular oedema secondary to central and branch RVO [1,41]. The optimal reinjection interval for dexamethasone implant is not yet well defined. Most case report data support 4 -- 6 months dosing intervals. However, there is large variability in the response of patients to treatment, likely related to multiple factors, including the subtype of occlusion and the duration of macular oedema; therefore, patients in clinical practice must be monitored and retreated as needed to prevent recurrence of macular oedema [47,48]. 4.
Promising strategies and new drugs
An ideal approach would involve agents with synergistic effects targeted to different components of RVO pathogenesis and possess complementary pharmacokinetic profiles. Combination therapy may be used as an alternative strategy in patients responsive to monotherapy or as an escalation modality in monotherapy-resistant cases. The potential benefits of combining different agents could be to decrease frequency and intensity of dosage, avoid cumulative doselimiting adverse events, or minimise reductions in efficacy due to tachyphylaxis. Currently, evidence of the efficacy of VEGF inhibitors combined with steroids or laser therapy are limited to small case series, short-term retrospective studies and uncontrolled data [49-51]. Moreover, many agents interfering with the multiple stimuli of the complex pathogenesis are in Phase I/II clinical trials. Some of these are directly addressed to influence with VEGF activity. Ziv-aflibercept (Zaltrap; Regeneron, Tarrytown, New York, USA) is an adaptive variant of aflibercept. Zaltrap was approved by FDA in August 2012 for the treatment of resistant metastatic colorectal carcinoma. Ziv-aflibercept has lower pH and higher osmolality when compared with aflibercept. A Phase I study is currently investigating its safety and efficacy when intravitreally administered in patients with macular oedema due to RVO [52]. 5.
Conclusion
Advances in medical research allowed to expand the therapeutic armamentarium in order to effectively and safely treat macular oedema secondary to both CRVO and BRVO. The development of intravitreal pharmacotherapy has revolutionised the management of RVO, whose treatment options were previously limited. However, patients treated with antiVEGF drugs need for repeated injections and frequent monitoring visits, while the use of corticosteroids lead to ocular side effects, such as cataract and increased IOP. Moreover,
several clinical trials comparing various pharmacological agents are being conducted. A combination of treatments may offer the best approach, but the evidence level is still low. Further studies are needed to better understand the pathogenic mechanisms underlying RVO in order to define the best treatment choice and the convenient dosing schedule to improve the long-term visual outcome in patients with macular oedema following BRVO and CRVO. 6.
Expert opinion
The introduction of novel drugs has clearly increased the therapeutic armamentarium of patients with macular oedema due to both CRVO and BRVO. Many clinical trials have shown that anti-VEGF agents and steroids may provide an improvement in visual acuity by two to four lines, and this outcome can be maintained over time [19,20,45,46]. However, some patients respond differently to therapy and the response also appears to be time dependent. As reported from GENEVA study, duration of macular oedema was a crucial factor influencing visual acuity gain after treatment. Each 1-month duration of macular oedema had an effect on the odds ratio for achieving at least a three-line improvement in visual acuity 6 months after treatment. This decrease in odds was about 14, 36, 60 and 84% for 1, 3, 6 and 12 additional months, respectively [53]. A post hoc analysis of CRUISE and BRAVO studies shows that > 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, < 50% of patients initially randomised to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains [54]. These data confirmed that a prompt treatment for macular oedema following RVO may be associated with better results in terms of visual acuity improvement. Long-term studies have reported that some eyes with RVO experience a progressive visual impairment due to the degeneration of photoreceptor cells. Now the major challenge is to focus on neuroprotective and stem cell-based therapies that may be able to regenerate the damaged photoreceptors and to improve sight in patients with a poor prognosis. Stem cell therapy is currently under investigation for the treatment of several retinal conditions, including macular oedema secondary to RVO [55].
Declaration of interest P Lanzetta has worked as a consultant for Alcon, Allegran, Bausch & Lomb, Bayer, Novartis and Roche. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitat de Girona on 01/19/15 For personal use only.
2.
Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion: consensus document. Ophthalmologica 2011;226:4-28
Kiire CA, Chong NV. Managing retinal vein occlusion. BMJ 2012;344:e499
4.
Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010;1172:313-19
6.
7.
Klein R, Klein BEK, Moss SE, et al. The epidemiology of retinal vein occlusion: the beaver dam eye study. Trans Am Ophthalmol Soc 2000;98:133-43 Klein R, Moss SE, Meuer SM, et al. The 15-year cumulative incidence of retinal vein occlusion: the beaver dam eye study. Arch Ophthalmol 2008;126:513-18
17.
18.
19.
20.
Frangieh GT, Green WR, BarraquerSoers E, et al. Histopathologic study of nine branch retinal vein occlusions. Arch Ophthalmol 1982;100:1132-40
8.
Haymore JG, Mejico LJ. Retinal vascular occlusion syndromes. Int Opthalmol Clin 2009;49:63-79
9.
Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost 2010;8:1886-94
10.
Justis P, Fekrat E, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol 2011;56:281-99
11.
Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol 2010;4:809-16
12.
Deobhakta A, Chang LK. Inflammation in retinal vein occlusion. Int J Inflam 2013;2013:438412
13.
The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271-82
14.
Wong TY, Scott IU. Retinal-vein occlusion. N Engl J Med 2010;363:2135-44
2382
16.
Golan S, Fisher N, Lowenstein A. Current treatment of retinal vein occlusion. Eur Ophthalmic Rev 2011;5:62-8
3.
5.
15.
21.
.
22.
.
Branch Vein Occlusion Study Group: argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol 1986;104:34-41 Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008;27:622-47 Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179-82 Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16:791-9 Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117:1124-33 Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117:1102-12 Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041-9 Randomised, double-masked, multicentre Phase III trial comparing monthly intravitreal injections of 0.3or 0.5-mg ranibizumab with sham injections in patients with macular oedema following central retinal vein occlusion (RVO). Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118:1594-602 Randomised, double-masked, multicentre Phase III trial comparing monthly intravitreal injections of Expert Opin. Pharmacother. (2014) 15(16)
0.3- or 0.5-mg ranibizumab with sham injections in patients with macular oedema following branch RVO. 23.
Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term followup in the HORIZON trial. Ophthalmology 2012;119:802-9
24.
Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology 2014;121:209-19 Open-label, single-arm, multicentre extension trial evaluating ranibizumab given as needed in patients with RVO.
.
25.
Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multicomponent, high- affinity blockers of cytokine action. Nat Med 2003;9:47-52
26.
Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99:11393-8
27.
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667-8
28.
Heier JS, Boyer D, Nguyen QD, et al. CLEAR- IT 2 Investigators: the 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor Trap-Eye dosed as needed after 12-week fixed dosing. Ophthalmology 2011;118:1098-106
29.
Nguyen QD, Shah SM, Browning DJ, et al. A phase I study of intravitreal vascular endothelial growth factor trapeye in patients with neovascular agerelated macular degeneration. Ophthalmology 2009;116:2141-8
30.
Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology 2012;119:1024-32
31.
Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol 2013;155:429-37
Pharmacotherapy for treatment of retinal vein occlusion
32.
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitat de Girona on 01/19/15 For personal use only.
33.
34.
.
35.
36.
37.
38.
39.
Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS Study. Ophthalmology 2014;121:1414-20 Large, multicentre, randomised clinical trial comparing sham versus intravitreal aflibercept for macular oedema due to central RVO. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 2013;97:278-84 Korobelnik JF, Holz FG, Roider J, et al. Intravitreal Aflibercept Injection for Macular Edema Resulting from Central Retinal Vein Occlusion: one-Year Results of the Phase 3 GALILEO Study. Ophthalmology 2014;121:202-8 Large, multicentre, randomised clinical trial comparing sham versus intravitreal aflibercept for macular oedema due to central RVO. Regeneron reports positive phase 3 data for Eylea (aflibercept) injection in macular edema following branch retinal vein occlusion. Tarrytown, NY; Regeneron. 2013. Available from: http://investor. regeneron.com/releasedetail.cfm? ReleaseID=798553 [Last accessed 14 July 2014] Wu L, Martı´nez-Castellanos MA, Quiroz- Mercado H; Pan-American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizu- mab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACO- RES). Graefes Arch Clin Exp Ophthalmol 2008;246:81-7 Iturralde D, Spaide RF, Meyerle CB. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26:279-84 Epstein DL, Algvere PV, von Wendt G, et al. Benefit from bevacizumab for macular edema in central retinal vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology 2012;119:2587-91
40.
to branch retinal vein occlusion: a systematic review. Graefes Arch Clin Exp Ophthalmol 2012;250:787-93
.
Hikichi T, Higuchi M, Matsushita T, et al. Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol 2014;98:195-9
47.
Kuppermann BD, Haller JA, Bandello F, et al. Onset and duration of visual acuity improvement after dexamethasone intravitreal with macular edema due to vein occlusion. Retina 2014. [Epub ahead of print]
48.
Querques G, Triolo G, Casalino G, et al. Retinal Venous Occlusions: diagnosis and Choice of Treatments. Ophthalmic Res 2013;49:215-22
49.
Riese J, Loukopoulos V, Meier C, et al. Combined intravitreal triamcinolone injection and laser photocoagulation in eyes with persistent macular edema after branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2008;246:1671-6
50.
Wang HY, Li X, Wang YS, et al. Intravitreal injection of bevacizumab alone or with triamcinolone acetonide for treatment of macular edema caused by central retinal vein occlusion. Int J Ophthalmol 2011;4:89-94
51.
Parodi MB, Iacono P, Ravalico G. Intravitreal triamcinolone acetonide combined with subthreshold grid laser treatment for macular oedema in branch retinal vein occlusion: a pilot study. Br J Ophthalmol 2008;92:1046-50
52.
Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol 2014;98:i11-16
53.
Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmology 2012;119:1190-8
54.
Thach AB, Yau L, Hoang C, et al. Time to clinically significant visual acuity gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials. Ophthalmology 2014;121:1059-66
55.
Clinical trial of autologous intravitreal bone-marrow CD34+ stem cells for retinopathy. Available from: http://
41.
Sarao V, Veritti D, Boscia F, et al. Intravitreal steroids for the treatment of retinal diseases. ScientificWorldJournal 2014;2014:989501
42.
Hou J, Tao Y, Jiang YR, et al. Intravitreal bevacizumab versus triamcinolone acetonide for macular edema due to branch retinal vein occlusion: a matched study. Chin Med J 2009;122:2695-9
43.
.
44.
.
45.
46.
Ip MS, Scott IU, Van Veldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:1101-14 Large, multicentre, randomised clinical trial comparing the standard care versus intravitreal triamcinolone acetonide for macular oedema due to central RVO. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion:the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:1115-28 Large, multicentre, randomised clinical trial comparing the standard care versus intravitreal triamcinolone acetonide for macular oedema due to branch RVO. Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134-49 Haller JA, Bandello F, Belfort R, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion.
Yilmaz T, Cordero-Coma M. Use of bevacizumab for macular edema secondary
Expert Opin. Pharmacother. (2014) 15(16)
Twelve-month study results. Ophthalmology 2011;118:2453-60 Randomised, multicentre clinical trial comparing 350- or 700-mg dexamethasone implant with sham injections in patients with macular oedema following RVO
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V. Sarao et al.
clinicaltrials.gov/show/NCT01736059 [Last accessed 14 July 2014]
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Affiliation Valentina Sarao1, Federica Bertoli1, Daniele Veritti1,2 & Paolo Lanzetta†1,2 MD † Author for correspondence 1 University of Udine, Department of Ophthalmology, Piazza Santa Maria della Misericordia, 33100 Udine, Italy Tel: +39 0432559907; Fax: +39 0432559904; E-mail: [email protected] 2 Istituto Europeo di Microchirugia Oculare (IEMO), Udine, Italy
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Expert Opin. Pharmacother. (2014) 15(16)
Pharmacotherapy for treatment of retinal vein occlusion Valentina Sarao, Federica Bertoli, Daniele Veritti & Paolo Lanzetta† University of Udine, Department of Ophthalmology, Udine, Italy
Introduction
2.
Anti-VEGF therapy
3.
Steroids
4.
Promising strategies and new drugs
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†
1.
5.
Conclusion
6.
Expert opinion
Introduction: Retinal vein occlusion (RVO) is a common vascular condition, which may cause blindness and impaired vision as a result of the development of macular oedema. The management of macular oedema due to RVO is complex and a multidisciplinary approach is required in order to limit disease progression and achieve a better clinical outcome. Areas covered: An update and a brief review on the current treatment strategies were provided in patients with macular oedema following RVOs. Evidence available from prospective, multicentre clinical studies evaluating the use of VEGF inhibitors and steroids and from a selective literature search is reported. Expert opinion: For many years, laser photocoagulation has been considered the standard of care for the treatment of branch RVO. However, new treatment modalities have been evaluated through randomised controlled trials. Recently, anti-VEGF agents and corticosteroids have been shown to be efficacious options in the treatment of RVO. Keywords: dexamethasone, laser, retinal vein occlusion, steroids, triamcinolone, VEGF. Expert Opin. Pharmacother. (2014) 15(16):2373-2384
1.
Introduction
Retinal vein occlusions (RVOs) are the second most common retinal vascular disease after diabetic retinopathy and can be divided into two primary categories depending on the site of obstruction: central RVO (CRVO) when the occlusion involves the whole central retinal vein, and branch RVO (BRVO) when the occlusion involves only one branch of the central retinal vein [1-3]. Population studies have estimated that there are about 520 cases of RVO per million population. These include 442 per million of BRVO and 80 per million of CRVO [4,5]. In the Beaver Dam Eye Study the 15-year cumulative incidence of CRVO and BRVO was 0.5 and 1.8%, respectively [6]. The pathogenesis of RVO is multifactorial and follows the principles of Virchow’s triad: stasis (generated by mechanical compression of the vein), damage to the vessel wall and hypercoagulability [1]. BRVO occurs at arterio-venous crossing sites that share a common adventitia [7]. CRVO is caused by external compression of the central retinal artery, which shares a common fibrous sleeve with the vein [8]. Thrombosis within a retinal vein leads to a partial obstruction of blood flow. The subsequent increased intraluminal pressure can lead to leakage of fluids and proteins across the vascular wall into the surrounding retinal tissue, resulting in local oedema. The increased interstitial oncotic pressure perpetuates tissue oedema, which impedes capillary perfusion and leads to ischemia. The stagnation of blood in the capillary induces hypoxia, which in turn causes damage to capillary endothelium that contributes to leakage of blood into the extracellular space. Furthermore, endothelial damage may result in a mild chronic inflammation of the affected vessels, with release of inflammatory mediators such as prostaglandins, leukotrienes, intercellular adhesion molecule 1 (ICAM-1), integrins TNF-a and VEGF. These cytokines weaken the blood--retinal barrier and help to perpetuate the oedema. 10.1517/14656566.2014.956083 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . .
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.
.
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Retinal vein occlusion (RVO) is a common vascular condition that may cause blindness and impaired vision. The management of macular oedema due to RVO is complex and a multidisciplinary approach is required in order to limit disease progression and achieve a better clinical outcome. Anti-VEGF agents may provide an improvement in visual acuity by two to four lines, and this outcome can be maintained over time (BRAVO, CRUISE, HORIZON, RETAIN, COPERNICUS, GALILEO). Steroids are effective in reducing central macular thickness and improving visual acuity, even if different side effects have been reported. (SCORE, GENEVA). The duration of macular oedema is a crucial factor influencing visual acuity gain after treatment: patients with lower duration of macular oedema showed the better functional results. Several clinical trials are being conducted to evaluate additional novel agents to treat macular oedema following RVO.
This box summarises key points contained in the article.
VEGF, in particular, has an important role in the disease. It is produced by retinal pigmented epithelial cells, endothelial cells, Mu¨ller cells and other ocular tissues in response to retinal hypoxia and binds to specific receptors on endothelial cells acting as a pro-angiogenetic and permeabilisating factor. Even if the primary venous obstruction is overcome via the formation of new collateral vessels, the macular oedema can persist for much longer due to a self-perpetuating cycle of VEGFinduced vascular permeability, which leads to macular oedema, capillary damage, and retinal ischemia, stimulating further release of VEGF and other inflammatory cytokines and causing chronic macular oedema. These cytokines constitute possible targets for new therapeutic strategies [9-12]. The main cause of visual loss in RVO is macular oedema [9]. In BRVO 50 -- 60% of eyes have a final visual acuity ‡ 5/10, even without treatment. In CRVO, usually visual acuity is poor at onset and declines further over time. Up to 34% of non-ischemic CRVO convert to ischemic forms within 3 years. Retinal neovascularisation may occur in 20% of non-perfused CRVO and 60% of those will develop neovascular glaucoma [1]. Visual acuity before treatment is an important prognostic factor. In particular, for eyes with an initial visual acuity ‡ 2.5/10 the prognosis is good even without treatment. Eyes with initial visual acuity £ 1/10 have a significantly worse prognosis compared to previous [1]. Macular grid laser photocoagulation represented the standard of care in patients with chronic macular oedema secondary to BRVO and visual acuity between 1/10 and 5/10 and if chosen it should be performed by 3 -- 6 months after the initial event and after resorption of most of the haemorrhages [13]. The Branch Vein Occlusion Study Group [13] remains today the largest international multicentre study that has demonstrated the effectiveness of grid photocoagulation 2374
in reducing macular oedema and improving visual acuity in patients with BRVO [9]. Macular laser photocoagulation is not recommended for the treatment of macular oedema in CRVO because it does not guarantee a significant improvement in visual acuity [14]. Panretinal photocoagulation of the ischemic retina is indicated both in BRVO and in CRVO if iris, retinal or disc neovascularisations are present. This treatment should be performed promptly to prevent the risk of neovascular glaucoma and vitreous haemorrhage [9,15]. 2.
Anti-VEGF therapy
RVO leads to an increased expression of VEGF by retinal pigment epithelium cells, causing neovascularisation and vascular hyperpermeability with subsequent breakdown of the blood--retina barrier and macular oedema [16]. The introduction of VEGF inhibitors is considered as the beginning of a new era in the treatment of macular oedema secondary to RVO targeting the disease at the causal molecular level. All three currently available anti-VEGF agents (ranibizumab, aflibercept, bevacizumab) have been applied successfully in reducing macular oedema due to RVO. A description of drugs that positively completed Phase III clinical trials are detailed in Tables 1 and 2. A short description is given below, and readers are referred to other studies for more details. Ranibizumab Ranibizumab (Lucentis; Genentech, Inc., San Francisco, CA, and Novartis AG, Basel, Switzerland) is a fragment of a recombinant, humanised, monoclonal antibody (48 kDa) that binds to and inhibits all the biologically active forms of VEGF-A [17,18]. Two randomised, double-masked, multicentre Phase III trials, the CRUISE and BRAVO studies, comparing monthly intravitreal injections of 0.3 or 0.5 mg ranibizumab with sham injections in patients with macular oedema following CRVO and BRVO [19-23]. The 6-month preliminary results showed in both studies a significant improvement in visual acuity in the treated groups versus the control groups with low rates of adverse side effects. This led to the FDA and EMA (European Medicines Agency) approval of ranibizumab 0.5 mg for the treatment of macular oedema secondary to BRVO and CRVO. In an open-label, single-arm, multicentre extension trial, the HORIZON study, patients who completed the CRUISE and BRAVO trials were evaluated at least every 3 months and treated with ranibizumab injections given as needed. Data were available for 181 patients at 12 months. Among patients with CRVO, visual acuity decreased by 4.2, 5.2 and 4.1 letters in the sham/0.5, 0.3/0.5 and 0.5 mg treatment groups, respectively, at the end of HORIZON trial. The mean number of ranibizumab injections was 2.9, 3.8 and 3.5, respectively. These data showed that the reduced frequency of ranibizumab injections in the second year was observed in 2.1
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92
68
104
30
63.8 13.3 67.4 12.4 67.5 2.0 69.2 12.8
±
±
±
±
59.9 ± 12.4
70.4 ± 10.4
70.6 ± 12.6
65.4 ± 13.1
130
30
67.6 ± 12.4
69.7 ± 11.6
67.5
65.5
Age (years ± SD)
130
132
73
114
Eyes (N)
88
12 months
12 months
12 months
12 months
12 months
Follow-up
Observation
CRVO
CRVO
CRVO
CRVO
CRVO
Disease
91
4-monthly PRN
6-weekly, then 6-weekly bevacizumab Monthly for 6 months, then IAI PRN
Monthly for 6 months, then IAI PRN Monthly for 6 months, then IAI PRN Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN 6-weekly
Regimen
TA 4 mg
TA 1 mg
Sham
Bevacizumab 1.25 mg/ Bevacizumab Sham/ Bevacizumab 1.25 IAI 2 mg
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg
Sham/IAI 2 mg
IAI 2 mg
Exposure
4
2.9
2.6
3
2.9
3.3
3.6
1.8
2.7
67.0
71.4
78.3
10.3
6.8
11.7
2
0
0
16.4
14.9
Capillary nonperfusion (%)
50.9 15.4 50.6 14.9 51.0 14.4 52.1 13.1
±
±
±
±
53.8 ± 15.6
43.9± 16.0
44.4 ± 15.3
49.2 ± 14.7
48.1 ± 14.6
47.4 ± 14.8
48.9 ± 14.4
50.7 ± 13.9
Mean BCVA (letters ± SD)
Baseline characteristics Duration ME (months)
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; CRT: Central retinal thickness; TA: Triamcinolone acetonide.
[43]
SCORE
[34]
GALILEO
Epstein et al.[38]
[21]
CRUISE
[31]
COPERNICUS
Study
Table 1. Summary of randomised clinical trials in retinal vein occlusions.
40
42
43
17.6
16.5
33.3
30
20
23
25
24.6
24.7
BCVA < 35 letters (%)
638 224 643 266 641 248 695 208
±
±
±
±
683 ± 234
729 ± 195
712 ± 330
687 ± 237
688 ± 253
679 ± 242
672 ± 245
661 ± 237
Mean CRT (mm ± SD)
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-12.1
-1.2
-1.2
+ 3.8
+ 16.9
+ 4.6
+ 16
+ 7.3
+ 13.9
+ 13.9
+ 3.8
+ 16.2
Mean BCVA change (letters ± SD)
6.8
25.6
26.5
32.4
60.2
33.3
60
33.1
50.8
47
30.1
55.3
0
2.0
2.2
10.5 ± 4.2
11.8 ± 2.8
9
9
3.7
3.3
3.8
3.2 ± 0.3
2.7 ± 0.2
Number of injections (mean ± SD)
Final outcomes BCVA gain > 15 letters (%)
-277
-261
-196
-219
-423
-404
-435
-427
-462
-452
-381
-413
Mean CRT change (mm ± SD)
Pharmacotherapy for treatment of retinal vein occlusion
2375
2376
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12 months
136
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg 67.5 ± 11.8 65.2 ± 12.7
132
±
±
±
±
131
134
67.2 12.4 68.1 10.6 67.4 11.2 66.6 11.2
63.9
426
137 BRVO
12 months
64.7
64.9
Age (years ± SD)
427
414
Eyes (N)
Grid Laser
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN
BRVO
12 months
Follow-up
3.7
3.3
3.6
4.5
4.6
4.1
5.2
5.2
5.1
Duration ME (months)
0
0
0
70.1
73.9
69.8
n/a
n/a
n/a
Capillary nonperfusion (%)
±
±
±
±
57.4 ± 12.2
53.0 ± 12.5
58.2 11.3 56.1 13.4 56.8 13.0 56.0 12.1
53.9 ± 10.4 54.3 ± 9.9 54.8 ± 9.9
Mean BCVA (letters ± SD)
Baseline characteristics
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; CRT: Central retinal thickness; TA: Triamcinolone acetonide.
[22]
BRAVO
[44]
RVO
Disease
138
TA 1 mg
SCORE
6-monthly PRN, then dexamethasone 0.7 mg 4-monthly PRN
6-monthly PRN
Regimen
TA 4 mg
Dexamethasone 0.35 mg Dexamethasone 0.7 mg Sham
GENEVA
[46]
Exposure
Study
Table 1. Summary of randomised clinical trials in retinal vein occlusions (continued).
6.8
9.9
6.7
24
25
20
n/a
n/a
n/a
BCVA < 35 letters (%)
±
±
±
±
488 ± 192
551 ± 223
521 198 516 160 537 198 522 201
555 ± 204 562 ± 188 539 ± 186
Mean CRT (mm ± SD)
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+ 12.1
+ 18.3
+ 16.4
+ 4.2
+ 4.0
+ 5.7
+4
+6
n/a
Mean BCVA change (letters ± SD)
43.9
60.3
56.0
28.9
27.2
25.6
21
24
n/a
BCVA gain > 15 letters (%)
9.1
8.4
8.5
0
2.1
2.2
1
2
n/a
Number of injections (mean ± SD)
Final outcomes
-273
-347
-313
-224
-170
-149
-267
-263
-263
Mean CRT change (mm ± SD)
V. Sarao et al.
Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
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Observation
TA 4 mg
TA 1 mg
Sham
4-monthly PRN
CRVO
88
91
92
68
Weeks 0 -- 24 Weeks 24 -- 52 Weeks 0 -- 24 Weeks 24 -- 52 Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
104
5.8%
14.4%
8.6%
n/a
3.5% 3.5% 5% 26% (‡ 35 mmHg) 8% 33% (‡ 35 mmHg) 1% 18% (‡ 35 mmHg)
5.9%
13.4%
8.7%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
1.8%
n/a
0%
0%
0%
7.0%
0%
n/a
1.7% 3.8%
n/a
n/a
0.9% 0%
n/a
4%
0%
4%
1.8%
1.5%%
1%
0%
n/a
n/a
1.8%
7%
5.4%
5.3%
3.3%
8.1%
0.9%
1.8%
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
0%
0%
0%
0%
0%
0%
0%
0.9%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
0%
0%
0%
0%
1%
0%
0%
0%
0%
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
0%
n/a
n/a
n/a
n/a
0%
0%
1.8%
0%
1.6%
0%
1.7%
1.4%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
1.8%
3.9%
1.6%
2.3%
0%
0%
0%
0.9%
2%
4%
9%
0%
0%
0%
1%
0%
0%
1.8%
7.0%
3.9%
1.5%
3.3%
8.1%
0%
0%
Iris Lens Vitreous Endophth- Pseudo- Rhegmato- Retinal Any tear intraocular neovascuDamage haemorrhage almitis endophthgenous almitis retinal inflammation larisation event detachment
0%
Cataract
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; IOP: Intraocular pressure; TA: Triamcinolone acetonide.
[43]
SCORE
[34]
Weeks 0 -- 48
30
6-weekly, then 6-weekly bevacizumab CRVO Monthly for 6 months, then IAI PRN
n/a
Weeks 3.88% 0 -- 24 Weeks 24 -- 52
130
Weeks 0 -- 48
Weeks 0 -- 52
8.5%
Weeks 12.3% 0 -- 24 Weeks 24 -- 52 Weeks 13.5% 0 -- 24 Weeks 24 -- 52 Weeks 8.3% 0 -- 52
Increased IOP
130
132
73
114
30
CRVO
CRVO
Disease Eyes Study (N) period
CRVO
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN 6-weekly
Monthly for 6 months, then IAI PRN
Sham/IAI 2 mg
Ranibizumab 0.3 mg
Monthly for 6 months, then IAI PRN
Regimen
IAI 2 mg
Exposure
Epstein Bevacizumab et al. [38] 1.25 mg/ Bevacizumab Sham/ Bevacizumab 1.25 GALILEO IAI 2 mg
[21]
CRUISE
[31]
COPERNICUS
Study
Table 2. Safety outcomes of randomised clinical trials in retinal vein occlusions.
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2377
2378
Exposure
Regimen
BRAVO
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Sham/ Ranibizumab 0.5 mg
Ranibizumab 0.5 mg
Ranibizumab 0.3 mg
Monthly for 6 months, then PRN Monthly for 6 months, then PRN Monthly for 6 months, then ranibizumab PRN BRVO
BRVO
RVO
Cataract
Weeks 2.3% 0 -- 24 Weeks 24 -- 52
132
6.9%
2% (‡ 35 mmHg) 14% (‡ 35 mmHg) 1% (‡ 35 mmHg) 5.2%
2.6%
3.1%
6.2%
4.5%
13%
35%
25%
n/a 19.8% (‡ 10 mmHg) 15.4% 29.8% (‡ 10 mmHg) 12.6% 12.5% (‡ 10 mmHg)
Weeks 0 -- 52
Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
Weeks 0 -- 52 Weeks 0 -- 52 Weeks 0 -- 52
Increased IOP
131
134
137
138
136
426
427
414
Disease Eyes Study (N) period
0%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
0.9%
4.6%
1.5%
5.2%
0%
0.7%
0.74%
n/a
n/a
n/a
0%
0%
0.8%
0%
0%
0.7%
0%
0%
0%
0%
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0%
0%
0%
0.7%
0%
0.7%
1.5%
n/a
n/a
n/a
0%
0%
0%
0.7%
0%
0.7%
0%
n/a
n/a
n/a
0.9%
3.1%
0%
2.2%
n/a
n/a
n/a
n/a
n/a
n/a
0%
2.3%
0.8%
0.7%
0%
0.7%
0%
n/a
n/a
n/a
Lens Vitreous Endophth- Pseudo- Rhegmato- Retinal Any Iris tear intraocular neovascuDamage haemorrhage almitis endophthgenous almitis retinal inflammation larisation detachment event
BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; IOP: Intraocular pressure; TA: Triamcinolone acetonide.
[22]
Grid Laser
GENEVA Dexamethasone 6-monthly 0.35 mg PRN [46] Dexamethasone 0.7 mg Sham 6-monthly PRN, then dexamethasone 0.7 mg TA 1 mg 4-monthly SCORE PRN TA 4 mg [44]
Study
Table 2. Safety outcomes of randomised clinical trials in retinal vein occlusions (continued).
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V. Sarao et al.
Pharmacotherapy for treatment of retinal vein occlusion
conjunction with worsening of outcome measures in CRVO patients. Many patients with CRVO who had substantial gains during 1 year of aggressive ranibizumab treatment may decline during a second year in which there is reduced frequency of injections and a less frequent monitoring visits [23,24]. Aflibercept Aflibercept (Eylea, previously known as VEGF-Trap Eye; Regeneron Pharmaceuticals, Tarrytown, NY, USA, and Bayer HealthCare, Berlin, Germany) is a novel anti-VEGF agent that recently gained FDA approval for the treatment of macular oedema due to CRVO. It is fully human recombinant fusion protein composed of the second Ig domain of VEGFR1 and the third Ig domain of VEGFR2, fused to the Fc region of human IgG1 [25]. Its binding affinity for VEGF is substantially greater than that of either bevacizumab or ranibizumab [26]. It could have a substantially longer duration of action in the eye [27], allowing for less frequent administration, as supported by early clinical trials [28-34]. Aflibercept was recently investigated in patients with macular oedema following BRVO. The VIBRANT trial was a double-masked, Phase III, randomised, active-controlled study of 183 patients with macular oedema secondary to BRVO [35]. Patients received randomly either 2 mg intravitreal aflibercept every 4 weeks or laser treatment, up to week 24. At week 24, 53% of treated eyes gained at least 15 letters of BCVA from baseline compared with 27% of laser-treated eyes (p < 0.001). The mean BCVA gain was of 17 letters in the treatment group at 24 weeks compared with 6.9 letters in the laser-treated group.
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2.2
Bevacizumab Bevacizumab (Avastin; Genentech, San Francisco, CA, USA, and Roche, Basel, Switzerland) is a full-length recombinant humanised monoclonal antibody against VEGF with 93% of its amino acid sequence derived from human IgG. Many uncontrolled case series have reported that intravitreal administration of bevacizumab can lead to a visual improvement and resolution of macular oedema following RVO [36,37]. However, because of the variation in dosing and treatment regimens among these studies, both long-term outcomes and safety data remain unclear [38]. Several short-term studies have reported the efficacy of bevacizumab in improving visual acuity and retinal thickness in patients with macular oedema following BRVO, even if the duration of action is often provisional and requires repeated injections [39]. Recently, a large case series have shown favourable 2-year results using bevacizumab to treat macular oedema due to BRVO. During the 2-year follow-up period, 105 patients received an intravitreal bevacizumab injection at baseline and then at physician’s discrection. At 24 months, the mean BCVA improved significantly by 0.3 LogMAR in 69% of 2.3
eyes (p = 0.001). The mean number of treatments at the end of the follow-up was 3.8 [40]. 3.
Steroids
The rationale for using corticosteroids for the treatment of macular oedema secondary to RVO is that these drugs have anti-inflammatory, anti-angiogenic, and anti-permeability properties. Steroids are thought to act by the induction of phospholipase A2, which reduces leukocyte chemotaxis and decreases levels of potent inflammatory cell mediators such as prostaglandins and leukotrienes. Corticosteroids have also been shown to reduce gene expression of pro-inflammatory mediators such as VEGF, TNF-a and other inflammatory chemokines, and induce the expression of anti-inflammatory factors such as pigment-derived growth factor. Additionally, they seem to reduce the expression of MMPs and to downregulate ICAM-1 on choroidal endothelial cells [41]. Triamcinolone acetonide Triamcinolone acetonide is a synthetic steroid of the glucocorticoid family. Data available in literature support its effectiveness in reducing macular oedema secondary to RVO [42]. The SCORE study (The Standard Care versus Corticosteroid for REtinal vein occlusion) consists of two multicentre, randomised, Phase III trials. The SCORE-CRVO study compared two different doses of intravitreal triamcinolone (1 and 4 mg) to the standard of care, represented by observation, in 271 eyes with CRVO. At 12 months, the proportion of patients who experienced a visual acuity gain of 15 letters or more was similar among the three groups (27% in the group treated with triamcinolone 1 mg, 26% in the group treated with the 4 mg dose and 7% in the control group). At month 24, however, a loss in visual acuity letter scores of 15 letters or more was noted in 48% of the observation group versus 31% of the triamcinolone 1 mg group and 26% of the triamcinolone 4 mg group. All three study groups showed similar optical coherence tomography (OCT)-measured centre point thickness decreases from baseline through follow-up with the exception of the month 4 visit. At 120 days, the percentage of participants with a centre point thickness inferior to 250 µm was greater in the 4 mg triamcinolone group and the median decrease in central retinal thickness was 196 µm in the 4 mg triamcinolone group, 77 µm in the 1 mg triamcinolone group and 125 µm in the observation groups (p < 001). In terms of safety, an increase in intraocular pressure (IOP) of at least 35 mmHg was noted in 5 and 8% of patients in the 1 and 4 mg triamcinolone doses, respectively, and in 1% of patients in the observation group. The percentage of eyes that initiated IOP-lowering medication through 12 months was 8% in the observation group, 20% in the 1 mg triamcinolone arm and 35% in the 4 mg triamcinolone group. Among eyes that were phakic at baseline, the estimate through month 12 of cataract formation or progression in the observation group was 18% compared with 26 and 33% for 3.1
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the 1 and 4 mg triamcinolone groups, respectively. While no eyes in the observation or 1 mg triamcinolone groups had cataract surgery through month 12, four eyes in the 4 mg group received cataract surgery. Similarly, cataract surgery was more frequent between months 12 and 24 in the 4 mg group, with 21 eyes receiving cataract surgery compared with 3 in the 1 mg group and 0 in the observation group [43]. The SCORE-BRVO study enrolled 411 patients with macular oedema secondary to BRVO and evaluated the efficacy of two different doses of intravitreal triamcinolone (1 and 4 mg) compared with grid laser photocoagulation. There was no significant difference in visual acuity among the three groups at 12 months. The percentage of eyes gaining > 3 Early Treatment Diabetic Retinopathy Study lines was 26, 27 and 29%, respectively. All three study groups showed OCT-measured centre point thickness decreases from baseline throughout follow-up. At the month 4 visit, the median decrease was 142 µm in the 4 mg triamcinolone group, 77 µm in the 1 mg group and 113 µm in the standard of care group. The follow-up instead showed that from month 12 to 36 mean improvement from baseline in visual acuity letter score was greater in the standard care group compared with the two triamcinolone groups (p < 0.05 at months 16, 20, 24 and 32, based on analysis of variance) and in the laser-treated group there was also a greater reduction of macular thickness. In terms of safety, at month 12, the rates of elevated IOP were similar for the observation and 1 mg groups, but higher in the 4 mg group: an increase in IOP of at least 35 mmHg was noted in 1, 2 and 14% of patients respectively. IOPlowering medication was initiated through 12 months in 41% of eyes in the 4 mg triamcinolone group, 7% of eyes in the 1 mg triamcinolone arm and 2% of eyes in the standard of care group. Among eyes that were phakic at baseline, incidence of cataract formation or progression through month 12 in the standard care group was 13% compared with 25 and 35% in the 1 and 4 mg triamcinolone arms, respectively. Through month 12, cataract surgery was reported for three participants in the standard of care group versus none in the 1 mg triamcinolone group and four in the 4 mg triamcinolone group. Cataract surgery was more frequent between months 12 and 24 in the 4 mg group, with 35 study eyes receiving such surgery, compared with 8 in the 1 mg study group and 6 in the standard of care group. The rates of cataract formation and IOP elevation, therefore, were higher in the steroid groups. Based on these data, the recommendation from the study was that laser remains the standard of care for BRVO [44]. Dexamethasone Dexamethasone intravitreal implant is a sustained-release formulation, which allows to achieve clinically effective concentrations of this drug directly into the vitreous. The use of a sustain-release implant is needed because dexamethasone, while having a 5 times greater anti-inflammatory potency than triamcinolone acetonide, shows a shorter intravitreal half-life. The 3.2
2380
GENEVA study (Global Evaluation of Implantable Dexamethasone in RVO with macular oedema) included two identical, multicentre, prospective, randomised, double-blind, 6-month, sham-controlled clinical trials. A total of 1267 patients with vision loss due to macular oedema associated with BRVO or CRVO were enrolled. In the 6-month initial treatment phase, patients were randomised to the administration of dexamethasone 700 µg (n = 427) or dexamethasone 350 µg (n = 414) or sham (n = 426). The proportion of patients that achieved an improvement in visual acuity of 15 or more letters was 22% in the 700 µg group, 23% in the 350 µg group and 13% in the sham group at month 3 (p < 0.001). These data were no longer statistically significant at month 6. Eyes receiving dexamethasone implant 0.7 or 0.35 mg achieved a 15-letter improvement in BCVA significantly faster than the eyes receiving sham treatment. The cumulative response rate for the time to reach a 15-letter improvement from baseline BCVA was 41% in the dexamethasone implant 0.7 mg group, 40% in the 0.35 mg group and 23% in the sham group (p < 0.001). The reduction in mean central retinal thickness was 208 ± 201 µm in the 700 µg group, 177 ± 197 µm in the 350 µg group and 85 ± 173 µm in the sham group at month 3 (p < 0.001) at day 180, but not statistically significant at month 6. In terms of safety, for both CRVO and BRVO patients, raised IOP peaked at month 2, but declined by month 3 and was close to 0% by month 6, with 19% of patients requiring an IOP-lowering agent and 0.7% of patients requiring a IOP-lowering surgical procedure. Similarly, rates of cataract progression were low, 7% progression at month 6 compared with 4% in the sham group [45]. In the extension open-label phase of the study, all eligible eyes received a 0.7-mg dexamethasone implant and were followed-up for additional 6 months. Retreatment criteria were: BCVA < 84 letters or retinal thickness of > 250 µm in the central subfield. The percentage of patients initially treated with dexamethasone 0.7 mg who required only a single treatment in 12 months of follow-up was 19%. The group that received a 0.7-mg dexamethasone implant during the first 6 months and a second 0.7 mg implant at day 180 had a 32% improvement in BCVA from baseline. Up to 27% of patients who were in the sham group during the first 6 months and were given their first 0.7 mg dexamethasone implant at day 180 had at least a 15-letter improvement in BCVA from baseline at visits during the open-label phase of the study. At 90 days after open-label treatment with dexamethasone implant 0.7 mg, the mean reduction in retinal thickness from baseline was 263 ± 219 µm in the retreated dexamethasone 0.35/0.7 mg group, 263 ± 217 µm in the retreated 0.7/0.7 mg dexamethasone group and 267 ± 206 µm in patients who received their first injection of dexamethasone implant. Over 12 months, cataract progression was found in 29.8% of phakic eyes that received two implants of 0.7 mg versus 5.7% of sham-treated phakic eyes; cataract surgery was performed in 1.3% of phakic eyes that received two implants of
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Pharmacotherapy for treatment of retinal vein occlusion
0.7 mg and in 1.1% of sham-treated phakic eyes. In eyes that received two of the 0.7 mg implants, an increase in IOP of at least 10 mmHg was seen in 12.6% of eyes after the first treatment and 15.4% of eyes after the second treatment [46]. Based on the GENEVA study results, intravitreal dexamethasone implant (Ozurdex) has become the first drug approved by the FDA and EMA for the treatment of macular oedema secondary to central and branch RVO [1,41]. The optimal reinjection interval for dexamethasone implant is not yet well defined. Most case report data support 4 -- 6 months dosing intervals. However, there is large variability in the response of patients to treatment, likely related to multiple factors, including the subtype of occlusion and the duration of macular oedema; therefore, patients in clinical practice must be monitored and retreated as needed to prevent recurrence of macular oedema [47,48]. 4.
Promising strategies and new drugs
An ideal approach would involve agents with synergistic effects targeted to different components of RVO pathogenesis and possess complementary pharmacokinetic profiles. Combination therapy may be used as an alternative strategy in patients responsive to monotherapy or as an escalation modality in monotherapy-resistant cases. The potential benefits of combining different agents could be to decrease frequency and intensity of dosage, avoid cumulative doselimiting adverse events, or minimise reductions in efficacy due to tachyphylaxis. Currently, evidence of the efficacy of VEGF inhibitors combined with steroids or laser therapy are limited to small case series, short-term retrospective studies and uncontrolled data [49-51]. Moreover, many agents interfering with the multiple stimuli of the complex pathogenesis are in Phase I/II clinical trials. Some of these are directly addressed to influence with VEGF activity. Ziv-aflibercept (Zaltrap; Regeneron, Tarrytown, New York, USA) is an adaptive variant of aflibercept. Zaltrap was approved by FDA in August 2012 for the treatment of resistant metastatic colorectal carcinoma. Ziv-aflibercept has lower pH and higher osmolality when compared with aflibercept. A Phase I study is currently investigating its safety and efficacy when intravitreally administered in patients with macular oedema due to RVO [52]. 5.
Conclusion
Advances in medical research allowed to expand the therapeutic armamentarium in order to effectively and safely treat macular oedema secondary to both CRVO and BRVO. The development of intravitreal pharmacotherapy has revolutionised the management of RVO, whose treatment options were previously limited. However, patients treated with antiVEGF drugs need for repeated injections and frequent monitoring visits, while the use of corticosteroids lead to ocular side effects, such as cataract and increased IOP. Moreover,
several clinical trials comparing various pharmacological agents are being conducted. A combination of treatments may offer the best approach, but the evidence level is still low. Further studies are needed to better understand the pathogenic mechanisms underlying RVO in order to define the best treatment choice and the convenient dosing schedule to improve the long-term visual outcome in patients with macular oedema following BRVO and CRVO. 6.
Expert opinion
The introduction of novel drugs has clearly increased the therapeutic armamentarium of patients with macular oedema due to both CRVO and BRVO. Many clinical trials have shown that anti-VEGF agents and steroids may provide an improvement in visual acuity by two to four lines, and this outcome can be maintained over time [19,20,45,46]. However, some patients respond differently to therapy and the response also appears to be time dependent. As reported from GENEVA study, duration of macular oedema was a crucial factor influencing visual acuity gain after treatment. Each 1-month duration of macular oedema had an effect on the odds ratio for achieving at least a three-line improvement in visual acuity 6 months after treatment. This decrease in odds was about 14, 36, 60 and 84% for 1, 3, 6 and 12 additional months, respectively [53]. A post hoc analysis of CRUISE and BRAVO studies shows that > 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, < 50% of patients initially randomised to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains [54]. These data confirmed that a prompt treatment for macular oedema following RVO may be associated with better results in terms of visual acuity improvement. Long-term studies have reported that some eyes with RVO experience a progressive visual impairment due to the degeneration of photoreceptor cells. Now the major challenge is to focus on neuroprotective and stem cell-based therapies that may be able to regenerate the damaged photoreceptors and to improve sight in patients with a poor prognosis. Stem cell therapy is currently under investigation for the treatment of several retinal conditions, including macular oedema secondary to RVO [55].
Declaration of interest P Lanzetta has worked as a consultant for Alcon, Allegran, Bausch & Lomb, Bayer, Novartis and Roche. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitat de Girona on 01/19/15 For personal use only.
2.
Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion: consensus document. Ophthalmologica 2011;226:4-28
Kiire CA, Chong NV. Managing retinal vein occlusion. BMJ 2012;344:e499
4.
Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010;1172:313-19
6.
7.
Klein R, Klein BEK, Moss SE, et al. The epidemiology of retinal vein occlusion: the beaver dam eye study. Trans Am Ophthalmol Soc 2000;98:133-43 Klein R, Moss SE, Meuer SM, et al. The 15-year cumulative incidence of retinal vein occlusion: the beaver dam eye study. Arch Ophthalmol 2008;126:513-18
17.
18.
19.
20.
Frangieh GT, Green WR, BarraquerSoers E, et al. Histopathologic study of nine branch retinal vein occlusions. Arch Ophthalmol 1982;100:1132-40
8.
Haymore JG, Mejico LJ. Retinal vascular occlusion syndromes. Int Opthalmol Clin 2009;49:63-79
9.
Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost 2010;8:1886-94
10.
Justis P, Fekrat E, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol 2011;56:281-99
11.
Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol 2010;4:809-16
12.
Deobhakta A, Chang LK. Inflammation in retinal vein occlusion. Int J Inflam 2013;2013:438412
13.
The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271-82
14.
Wong TY, Scott IU. Retinal-vein occlusion. N Engl J Med 2010;363:2135-44
2382
16.
Golan S, Fisher N, Lowenstein A. Current treatment of retinal vein occlusion. Eur Ophthalmic Rev 2011;5:62-8
3.
5.
15.
21.
.
22.
.
Branch Vein Occlusion Study Group: argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol 1986;104:34-41 Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008;27:622-47 Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179-82 Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16:791-9 Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117:1124-33 Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117:1102-12 Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041-9 Randomised, double-masked, multicentre Phase III trial comparing monthly intravitreal injections of 0.3or 0.5-mg ranibizumab with sham injections in patients with macular oedema following central retinal vein occlusion (RVO). Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118:1594-602 Randomised, double-masked, multicentre Phase III trial comparing monthly intravitreal injections of Expert Opin. Pharmacother. (2014) 15(16)
0.3- or 0.5-mg ranibizumab with sham injections in patients with macular oedema following branch RVO. 23.
Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term followup in the HORIZON trial. Ophthalmology 2012;119:802-9
24.
Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology 2014;121:209-19 Open-label, single-arm, multicentre extension trial evaluating ranibizumab given as needed in patients with RVO.
.
25.
Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multicomponent, high- affinity blockers of cytokine action. Nat Med 2003;9:47-52
26.
Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99:11393-8
27.
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667-8
28.
Heier JS, Boyer D, Nguyen QD, et al. CLEAR- IT 2 Investigators: the 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor Trap-Eye dosed as needed after 12-week fixed dosing. Ophthalmology 2011;118:1098-106
29.
Nguyen QD, Shah SM, Browning DJ, et al. A phase I study of intravitreal vascular endothelial growth factor trapeye in patients with neovascular agerelated macular degeneration. Ophthalmology 2009;116:2141-8
30.
Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology 2012;119:1024-32
31.
Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol 2013;155:429-37
Pharmacotherapy for treatment of retinal vein occlusion
32.
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Universitat de Girona on 01/19/15 For personal use only.
33.
34.
.
35.
36.
37.
38.
39.
Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS Study. Ophthalmology 2014;121:1414-20 Large, multicentre, randomised clinical trial comparing sham versus intravitreal aflibercept for macular oedema due to central RVO. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 2013;97:278-84 Korobelnik JF, Holz FG, Roider J, et al. Intravitreal Aflibercept Injection for Macular Edema Resulting from Central Retinal Vein Occlusion: one-Year Results of the Phase 3 GALILEO Study. Ophthalmology 2014;121:202-8 Large, multicentre, randomised clinical trial comparing sham versus intravitreal aflibercept for macular oedema due to central RVO. Regeneron reports positive phase 3 data for Eylea (aflibercept) injection in macular edema following branch retinal vein occlusion. Tarrytown, NY; Regeneron. 2013. Available from: http://investor. regeneron.com/releasedetail.cfm? ReleaseID=798553 [Last accessed 14 July 2014] Wu L, Martı´nez-Castellanos MA, Quiroz- Mercado H; Pan-American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizu- mab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACO- RES). Graefes Arch Clin Exp Ophthalmol 2008;246:81-7 Iturralde D, Spaide RF, Meyerle CB. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26:279-84 Epstein DL, Algvere PV, von Wendt G, et al. Benefit from bevacizumab for macular edema in central retinal vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology 2012;119:2587-91
40.
to branch retinal vein occlusion: a systematic review. Graefes Arch Clin Exp Ophthalmol 2012;250:787-93
.
Hikichi T, Higuchi M, Matsushita T, et al. Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol 2014;98:195-9
47.
Kuppermann BD, Haller JA, Bandello F, et al. Onset and duration of visual acuity improvement after dexamethasone intravitreal with macular edema due to vein occlusion. Retina 2014. [Epub ahead of print]
48.
Querques G, Triolo G, Casalino G, et al. Retinal Venous Occlusions: diagnosis and Choice of Treatments. Ophthalmic Res 2013;49:215-22
49.
Riese J, Loukopoulos V, Meier C, et al. Combined intravitreal triamcinolone injection and laser photocoagulation in eyes with persistent macular edema after branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2008;246:1671-6
50.
Wang HY, Li X, Wang YS, et al. Intravitreal injection of bevacizumab alone or with triamcinolone acetonide for treatment of macular edema caused by central retinal vein occlusion. Int J Ophthalmol 2011;4:89-94
51.
Parodi MB, Iacono P, Ravalico G. Intravitreal triamcinolone acetonide combined with subthreshold grid laser treatment for macular oedema in branch retinal vein occlusion: a pilot study. Br J Ophthalmol 2008;92:1046-50
52.
Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol 2014;98:i11-16
53.
Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmology 2012;119:1190-8
54.
Thach AB, Yau L, Hoang C, et al. Time to clinically significant visual acuity gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials. Ophthalmology 2014;121:1059-66
55.
Clinical trial of autologous intravitreal bone-marrow CD34+ stem cells for retinopathy. Available from: http://
41.
Sarao V, Veritti D, Boscia F, et al. Intravitreal steroids for the treatment of retinal diseases. ScientificWorldJournal 2014;2014:989501
42.
Hou J, Tao Y, Jiang YR, et al. Intravitreal bevacizumab versus triamcinolone acetonide for macular edema due to branch retinal vein occlusion: a matched study. Chin Med J 2009;122:2695-9
43.
.
44.
.
45.
46.
Ip MS, Scott IU, Van Veldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:1101-14 Large, multicentre, randomised clinical trial comparing the standard care versus intravitreal triamcinolone acetonide for macular oedema due to central RVO. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion:the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:1115-28 Large, multicentre, randomised clinical trial comparing the standard care versus intravitreal triamcinolone acetonide for macular oedema due to branch RVO. Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134-49 Haller JA, Bandello F, Belfort R, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion.
Yilmaz T, Cordero-Coma M. Use of bevacizumab for macular edema secondary
Expert Opin. Pharmacother. (2014) 15(16)
Twelve-month study results. Ophthalmology 2011;118:2453-60 Randomised, multicentre clinical trial comparing 350- or 700-mg dexamethasone implant with sham injections in patients with macular oedema following RVO
2383
V. Sarao et al.
clinicaltrials.gov/show/NCT01736059 [Last accessed 14 July 2014]
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Affiliation Valentina Sarao1, Federica Bertoli1, Daniele Veritti1,2 & Paolo Lanzetta†1,2 MD † Author for correspondence 1 University of Udine, Department of Ophthalmology, Piazza Santa Maria della Misericordia, 33100 Udine, Italy Tel: +39 0432559907; Fax: +39 0432559904; E-mail: [email protected] 2 Istituto Europeo di Microchirugia Oculare (IEMO), Udine, Italy
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