Thomson

The treatment of branch retinal vein occlusion with bevacizumabFederico Badala` Microchirurgia Oculare del Mediterraneo & Associati New treatment modalities for branch retinal vein occlusion have recently been introduced. The role of intravitreal bevacizumab injections will be discussed and Microchirurgia Oculare del Mediterraneo & Associati compared with laser photocoagulation and other novel intravitreal pharmacotherapies.
(MOMA), Via Angelo Brofferio 7, Roma 00195, ItalyTel: +39 349 8712525; fax: +39 06 3725242; Argon laser photocoagulation is the single treatment for branch retinal vein occlusionthat has been shown to reduce vision loss in a randomized controlled clinical trial. The effectiveness of this treatment is limited though. Currently, increasing data support the role of intravitreal bevacizumab as an effective treatment for patients with macularedema secondary to branch retinal vein occlusion. Multiple injections seem to benecessary in order to achieve visual stabilization, favorable and durable macularchanges. The effect of a single injection seems to last 6–8 weeks. The most commontreatment protocol is two to three injections over the first 5–6 months. Patients who hadminimal or no response to laser therapy appeared to benefit from bevacizumab. Nosignificant complications have been associated with its use but only short-term data areavailable.
SummaryIntravitreal bevacizumab appears to be a safe and effective treatment for macular edemaassociated with branch retinal vein occlusion, at least in the short term. Furtherrandomized, controlled investigations are needed to assess long-term safety andefficacy of intravitreal bevacizumab.
Keywordsavastin, bevacizumab, branch retinal vein occlusion, macular edema Curr Opin Ophthalmol 19:234–238ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins The BRVO study evaluated whether macular grid laser photocoagulation could improve vision in patients Branch retinal vein occlusion (BRVO) is a common with macular edema secondary to BRVO and vision retinal vascular disorder affecting mostly subjects over between 20/40 and 20/200. One hundred and thirty- 50 years of age This condition is characterized by nine eyes were randomized to either treatment or obser- sectoral intraretinal hemorrhages, retinal ischemia, retinal vation. After an average follow-up of 3.1 years, treated exudates and macular edema. The site of occlusion is eyes presented with a mean visual acuity of 20/40 to typically located at an arterio-venous crossing site. Vision 20/50, in which the mean visual acuity among controls is usually decreased by a variety of mechanisms: capillary was 20/70 (the difference was statistically significant nonperfusion and increased hydrostatic pressure that with P < 0.0001). Further data analysis suggested results in hemorrhages and fluid exudation. The presence that the smaller the interval between the onset of of fluid within the macula (macular edema) is the most common cause of vision loss in this group of patients outcome: two or more lines of vision were gained by70% of patients treated within the first 12 monthscompared with only 32% of patients treated after photocoagulationTreatments in BRVO have two main goals: to reducemacular edema and to prevent retinal neovascularization Unfortunately patients with acute symptoms (less than caused by ischemia. Currently the only evidence-based 3 months of onset) were not evaluated in the study on therapy for BRVO is argon laser photocoagulation. This is the basis of the assumption that they will spontane- the single treatment that has been shown to reduce vision ously improve during that period. This leaves an import- loss in a randomized controlled clinical trial  ant question unanswered: whether starting treatment 1040-8738 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins immediately after development of symptoms could make for intravenous use in metastatic colon cancer. Since 2005, it has been given off-label via intravitreal injectionsin patients with macular degeneration. Patients with Two interesting studies by Battaglia-Parodi and colleagues retinal vein occlusion present increased intravitreal levels attempted to address this issue. One study compared of VEGF Recently, intravitreal injections of bevaci- the efficacy of macular grid laser photocoagulation versus zumab have been documented to improve visual acuity observation in patients with less than 15 days of symptoms.
and reduce macular edema in patients with retinal vein Seventy-seven eyes were randomized to either treatment or no treatment and after 12 months of follow-up bothgroups showed improved visual acuity without significant A few retrospective studies have reported short-term safety and efficacy of intravitreal bevacizumab injectionsin patients with macular edema secondary to branch The second study evaluated whether in cases of acute retinal vein occlusion. In the case series from Rabena BRVO (less than 15 days of symptoms) the visual outcome et al. the clinical course of 27 eyes treated with could be influenced by treatment timing. One-hundred intravitreal bevacizumab 1.25 mg/0.05 ml is presented.
and thirty-seven eyes were randomized to either early During a mean follow-up of approximately 5 months grid laser photocoagulation (3 months after diagnosis) patients received on average two injections. Visual acuity delayed photocoagulation (6–18 months after diagnosis) improved from 20/200 at baseline to 20/100 at 1 month, or no treatment. After 2 years of follow-up the visual acuity 3 months and last visit. The mean central macular thick- improved in all groups without significant differences ness was 478 mm at baseline and decreased to 310, 336 among them. The authors of these two studies conclude and 332 mm at 1 month, 3 months and last visit. Interest- that grid laser photocoagulation of the macular region does ingly, among these patients more than 80% had limited or not significantly impact the natural course of the disease.
no response to prior treatment with either macular grid Since the authors of these reports did not perform pre- laser (63%) or intravitreal triamcinolone acetonide injec- study power calculations it remains uncertain whether the tions (22%). The time between BRVO diagnosis and studies where sufficiently powered to detect a difference.
treatment with bevacizumab was approximately 2 yearson average.
Another important conclusion of the BRVO study wasthat peripheral scatter laser photocoagulation can effec- We reviewed our experience with 16 patients with macu- tively reduce development of neovascularization and lar edema secondary to BRVO treated with intravitreal vitreous hemorrhage. Four hundred and one eyes were bevacizumab 1.25 mg/0.05 ml and found similar results assigned randomly to either a treated or an untreated (F. Badala, et al. ARVO meeting 2007; personal com- control group. After an average follow-up time of 4 years munication). Over a mean follow-up of almost 5 months the development of neovascularization and vitreous patients received 2.5 injections on average. Mean visual hemorrhage was significantly less in treated eyes. Even acuity improved from 20/230 at baseline to 20/70 and though the study was not designed to determine whether 20/50 at 1 month and last visit, respectively. Mean central peripheral scatter treatment should be applied before macular thicknesses have been reduced from 505 mm at rather than after the development of neovascularization, baseline to 267 and 273 mm at 1 month and last visit, the authors suggested that peripheral scatter photocoa- respectively. Interestingly, 25% of our patients who failed gulation should be applied after the development of to respond intravitreal triamcinolone or laser grid photo- neovascularization rather than before.
coagulation improved after intravitreal bevacizumab.
The average time between BRVO diagnosis and treat-ment with bevacizumab was about 1 year.
New treatments: intravitrealpharmacotherapy To date there are three prospective studies published on Laser photocoagulation has been the only evidence-based the role of intravitreal bevacizumab after BRVO. Schaal treatment for patients with macular edema secondary to and colleagues prospectively evaluated 40 patients BRVO since 1984 when the BRVO study was published.
[22 with BRVO, 18 with central retinal vein occlusion Recently there have been increasing data supporting (CRVO)] with macular edema secondary to vein occlu- intravitreal pharmacotherapies as a valid adjunct if not sion who received 2.5 mg of intravitreal bevacizumab.
an alternative to standard laser photocoagulation.
The injections were repeated every 6 weeks when per-sistent or recurring macular edema was noted. Over a Bevacizumab (Avastin; Genentech Inc., San Francisco, mean follow-up of approximately 6 months each patient California, USA) is a monoclonal antibody to vascular received on average 2.6 injections. On the last visit, 77% endothelial growth factor (VEGF) that has been of patients with BRVO had significantly improved vision approved by the Food and Drug Administration (FDA) (at least three lines) and the mean central macular thickness had significantly been reduced from an average The literature available seems to indicate that multiple injections are usually needed to achieve visual acuitystabilization, favorable and durable macular changes.
Pai et al. prospectively studied 21 patients with Two to three injections over the first 5–6 months appear macular edema secondary to vein occlusion (12 with to be the most common treatment protocol  BRVO, nine with CRVO). Patients received a single Peak visual acuity appears to be reached during the first 1.25 mg bevacizumab injection and were followed for 3 months. Mean visual acuity improved from 20/381 at postoperative seems to be a critical interval for reinjection baseline to 20/135 and 20/178 at 1 and 3 months, respect- in order to stabilize vision Some authors suggest ively. The central macular thickness decreased from a performing OCT scans between 3 and 6 weeks after mean of 647 mm at baseline to 293 mm at 1 month and treatment to help decide on the best re-injection time 320 mm at the last visit. There was no significant difference The amount of medication injected does not seem in the visual outcome between the BRVO and the CRVO to significantly impact the outcome (three different dosing regimens have been utilized: 1.25 mg 2.0 mg and 2.5 mg There seems to be pivotal The German group of Schaal and collaborators evidence that initiation of therapy early after the onset of prospectively evaluated the response of a single bevaci- symptoms is associated with a better visual outcome zumab treatment in 21 eyes with vein occlusion (14 with Theoretically, though, the use of anti-VEGF medications CRVO, seven with BRVO). Patients were followed for early after diagnosis could suppress the development 9 weeks; the mean visual acuity improved by more than of collateral vessels and have a negative impact on the two lines compared with baseline. The peak visual long-term vision. After myocardial ischemia, for example, acuity was reached between 3 and 6 weeks after injection, the expression of VEGF is critical for development of while a decrease in visual acuity was observed between coronary collaterals So far, treatment with intra- weeks 6 and 9. The authors conclude that since the vitreal bevacizumab does not seem to worsen perfusion decrease of visual acuity was anticipated by macular dynamics after retinal vein occlusion Moreover, thickness increase, OCT examinations between weeks bevacizumab appears to be effective also in patients who 3 and 6 may be helpful in judging the appropriate time for had minimal or no response to prior laser or intravitreal reinjection. Subgroup analysis showed that patients receiving treatment within the first 3 months after onsetof symptoms gained on average four lines of visual acuity These results are encouraging and warrant further inves- compared with an average of 1.8 and 2.5 gain for patients tigation. Short follow-up and the lack of a control group, who received treatment later in the course of the disease however, are major limitations of all the studies on intra- (4–6 months and more than 6 months after diagnosis, vitreal bevacizumab after BRVO and limit generalizability respectively). The latter finding may represent the of these results. Convincing evidence could only come natural tendency for visual acuity to improve early in from a randomized controlled clinical trial. Currently, a the course of the disease, but also raises the question of phase II, randomized controlled trial is recruiting whether early treatment may be associated with a more patients with macular edema secondary to BRVO in Iran; the study will be comparing intravitreal injections ofbevacizumab with sham controls.
None of the above mentioned studies described sig-nificant complications after intravitreal bevacizumab A comparison of intravitreal bevacizumab with laser treat- injections including endophthalmitis, increased intra- ment for macular edema secondary to branch retinal vein ocular pressure, retinal tears, retinal detachments or occlusion is difficult. Bevacizumab appears to be effective retinal pigment epithelial rips. A restrospective case in patients with acute and chronic BRVO; some authors series from the group of Matsumoto and colleagues reported efficacy up to more than 3 years after diagnosis reported on rebound macular edema following while apparently the best outcome is associated with intravitreal bevacizumab in three patients with retinal early treatment. Likewise, laser treatment seems to be vein occlusion (1 BRVO, 2 CRVO). These patients more effective when applied in the first year after BRVO, presented with macular edema that initially responded but the BRVO study did not evaluate patients with acute to intravitreal bevacizumab but subsequently recurred in symptoms (patients included were at least 3 months after excess of that observed at baseline. The authors conclude diagnosis) In contrast with laser treatment, the use of that in some cases frequently repeated injections may be bevacizumab is not limited by presence of macular hemor- required to prevent a rebound phenomenon with no rhages. In addition to that, patients who had limited or no clearly defined endpoint and recommend caution with response to laser showed improvement after intravitreal the use of anti-VEGF treatments until long-term safety bevacizumab Whether bevacizumab can improve vision on a long-term basis still remains to be addressed, while the efficacy of laser treatment has been documented tears or detachments have been associated with the use well after 3 years of treatment. The inclusion criteria in the of intravitreal bevacizumab after BRVO, but only short- BRVO study did not permit entry of patients with less term data are available. Bevacizumab seems to be safer than 20/200 vision; intravitreal bevacizumab case series than other intravitreal medications like triamcinolone and document reduced macular edema and improved visual tissue plasminogen activator, which have been described acuity in patients with much worse vision (counting to improve vision in patients with macular edema second- fingers) at baseline. The BRVO study showed that ary to BRVO but carry potential side effects, such as peripheral scatter laser photocoagulation can effectively increased intraocular pressure, cataract progression and reduce development of neovascularization and vitreous hemorrhage; evidence of whether bevacizumab has a rolein these regards remains anecdotal. Despite this, the short All the studies on bevacizumab and BRVO are noncon- follow-up and limited numbers of all bevacizumab series trolled and have a short follow-up, which limit general- preclude a direct comparison between the current standard izability of their results; nevertheless, preliminary data are of care of laser treatment and the new promising intra- encouraging and warrant further investigation. If a randomized controlled clinical trial confirms the long-termsafety and efficacy of bevacizumab this intervention may Intravitreal triamcinolone acetonide (IVTA) has been replace laser therapy as the standard of care for BRVO shown to be effective in improving vision and reducing macular edema secondary to BRVO but its use isoften associated with cataract formation and increasedintraocular pressure The long-term safety and efficacy of IVTA are currently being investigated in a Papers of particular interest, published within the annual period of review, have multicenter clinical trial known as the Standard Care Versus Corticosteroid for Retinal Vein Occlusion Study (SCORE). The study is recruiting over 400 patients that Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 267).
will be randomized to laser treatment, IVTA 4 mg or IVTA1 mg. Another multicenter randomized trial is evaluating The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984; 98:271–282.
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intravitreally to treat macular edema secondary to BRVO.
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This is a retrospective review that well elucidates most of the characteristics injection seems to last 6–8 weeks. The most common features of bevacizumab treatment after BRVO. Twenty-seven cases responded to treatment protocol is two to three injections over the first bevacizumab 1.25mg. More than 80% of patients failed prior laser treatment orintravitreal steroids.
5–6 months. Patients who have minimal or no response to 11 Stahl A, Agostini H, Hansen LL, Feltgen N. Bevacizumab in retinal vein laser therapy or intravitreal steroids appear to benefit from occlusion-results of a prospective case series. Graefes Arch Clin Exp bevacizumab. No significant complications, including In this prospective case series using 2.5 mg of intravitreal bevacizumab there was a endophthalmitis, increased intraocular pressure, retinal similar response as to intravitreal bevacizumab 1.25 mg.
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retinal vein occlusion: an evidence-based systematic review. Ophthalmology

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