Anti-VEGF vs Macular Grid Photocoagulation for Retinal Vein Occlusion
RITA EHRLICH, MD ∙ RUTH AXER-SIEGEL, MD ∙ THOMAS A. CIULLA, MD ∙ ALON HARRIS, PhD ∙ DOV WEINBERGER, MD
Retinal vein occlusion is the second most common cause of adult-acquired retinal vascular disease. Pooled data from population-based studies reported a prevalence of four per 1,000 for branch vein occlusion (BRVO) and 0.8 per 1,000 for central retinal vein occlusion (CRVO). It is estimated that 14 million patients are affected by BRVO world wide and another 2.5 million patients affected by CRVO.1
Retinal vein occlusion is classified into central, hemicental, and branch RVO.2 Macular edema is a frequent cause for vision loss in patients with RVO. Macular edema following RVO is caused by flux of fluids from the blood vessels due to breakdown of the inner blood retinal barrier, as a result of damage to the tight junctions between the endothelial cells of the retinal capillaries.3 Increased levels of vascular endothelial growth factor were found in patients with RVO, in correlation with increased retinal vascular permeability.4,5
Several treatment modalities for RVO have been investigated in the last two decades, including laser treatment, intravitreal injections of both steroids and anti-VEGF drugs, and vitrectomy surgery (including radial optic neurotomy for CRVO and sheathotomy for BRVO).6 In the current review, we will focus on laser treatment vs intravitreal anti-VEGF injections.
Figure 1. Typical nonischemic central retinal vein occlusion in the left eye of a 48-year-old African-American male.
CENTRAL RETINAL VEIN OCCLUSION
The Central Vein Occlusion Study compared laser treatment to observation in CRVO. The study found no significant difference in visual outcomes between the macular grid treatment and observation groups at any follow-up points.7 The natural history of eyes with macular edema due to CRVO is not favorable, with 43% of patients losing ≥15 letters and an average loss of 12 letters at 12 months of follow-up. Only 6.8% of patients experience a gain of ≥15 letters without treatment.8
Currently, there is no gold standard treatment for macular edema due to CRVO, and in recent years several treatment modalities have been investigated. Anti-VEGF treatment in CRVO has gained interest in the last decade. In a retrospective study of 10 patients with CRVO who were treated by intravitreal bevacizumab (Avastin, Genentech) and were followed up for two years, better short-term visual acuity gain was reported compared to long-term gain, with 2.9 lines gained at three weeks and only 1.6 lines of long-term gain. Good response to the first injection and low baseline visual acuity correlated positively with higher long-term visual acuity gains. Furthermore, visual acuity with bevacizumab treatment was not always maintained over a two-year period, despite repeated injections.9
Another small case series with a mean follow-up of less than 12 months reported favorable visual acuity outcomes and improvement in central macular thickness in patients with CRVO.10-12 Hoeh et al.13 reported a 50% de crease in central retinal thickness and visual acuity improvement of 1.9 ±3.2 lines in a series of CRVO patients, with mean follow-up of 60 weeks. Macular edema resolved without recurrence in 33% of the patients during more than 25 weeks, resolved and recurred in one-third, and did not resolve completely in one-third of the patients at any follow-up visit after receiving a minimum of three injections. One-third of the patients with CRVO did not show improvement in vision. Younger age and better initial visual acuity correlated to the final VA . Gregori et al.14 also reported favorable response to bevacizumab treatment: in their study, one-third of the patients completed 12 months of follow-up with a mean gain of nine letters in vision.
In contrast, Beutel et al.15 showed no improvement in visual acuity after 12 months of follow-up in patients with CRVO, despite improvement in central macular thickness. Similar results in patients with CRVO were reported in another study with 12 months of follow-up on a small number of patients.16
Ranibizumab (Lucentis, Genentech) was first investigated in a small series of patients with CRVO and showed promising results. In a study on 20 patients with CRVO receiving three monthly injections of ranibizumab over three months of follow-up, macular thickness was reduced markedly and visual acuity improved.17 Small prospective studies with 12 months of follow-up supported these results. Patients required repeated injections of ranibizumab during the 12 months, with a mean of 7.4 to 8.5 injections.18,19
The CRUISE study — a phase 3, multicenter, randomized study in CRVO — randomized 392 patients to 0.3 mg, 0.5 mg ranibizumab or sham injections monthly for six months. The study reported good results of 12.7- and 14.9-letter gains (0.3 mg and 0.5 mg, respectively), compared to only 0.8 letters in the sham injection arm. In addition, 46% to 48% of eyes in the both groups gained 15 or more letters at six months vs 17% of sham-treated eyes.
In a phase 2 randomized trial of pegaptanib sodium (Macugen, Eyetech) for treatment of macular edema secondary to CRVO, the mean number of letters gained were +9.9, +7.1 and −3.2 for the 1-mg, 0.3-mg and sham groups, respectively. Macular thickness was reduced by −243 µm, −179 µm and −148 µm in the 1-mg, 0.3-mg and sham groups, respectively.20
The SCORE study of CRVO8 — a multicenter, randomized clinical trial of 271 participants — compared intravitreal triamcinolone acetonide 1 mg and 4 mg to observation. The study found that 26% to 27% of patients treated with 4 mg and 1 mg of intravitreal triamcinolone had improvement of 15 letters or more of vision compared to 7% in the observation group. At month 24, 48% of patients in the observation group (compared to 30% in the treatment groups) lost 15 letters of vision. The safety profile of 4 mg intravitreal triamcinolone was less favorable than the 1-mg dose, and one-third of eyes in the 4-mg triamcinolone group required intraocular pressure-lowering medication through 12 months.
Figure 2. Laser photocoagulation remains the standard of care for branch retinal vein occlusions, although new data highlight the expanded role of medical therapy.
BRANCH RETINAL VEIN OCCLUSION
The Branch Vein Occlusion Study demonstrated the benefit of macular grid photocoagulation in macular edema associated with BRVO. However, although 65% of patients had two or more lines gain in vision, 40% of treated eyes had visual acuity worse than 20/40 and 12% worse than 20/200 after three years of follow-up.21 This has set the search for additional treatment options in the last decade. In the recent SCORE-BRVO study, a multicenter, randomized clinical trial that compared macular laser treatment to 1 mg and 4 mg of intravitreal triamcinolone, patients required 1.8 laser treatments over 12 months of follow-up and 27% of patients required the maximum of three treatments over that period of time. Dense macular hemorrhages precluding macular grid at baseline were found in 28.5% of patients.
After 12 months of follow-up, 29% of patients treated with laser gained ≥15 letters and 15% of patients lost ≥15 letters of vision. In the triamcinolone treatment group, 26% to 27% of participants gained 15 letters or more in vision. The study did not find difference in visual acuity at 12 months between the treatment groups. However, rates of adverse events, such as elevated IOP and cataract, were highest in the 4-mg group.22 The median central retinal thickness measure on OCT decreased in the laser treatment group from 501 µm to 228 µm at 12 months.22
A retrospective study of 88 patients with macular edema associated with BRVO examined the outcome of patients requiring multiple laser treatment. Grid laser photocoagulation was carried out in patients with intact perifoveal capillaries and after resolution of intraretinal hemorrhages.23 Two laser sessions were required in 52% of patients, three laser sessions were required in 17%, and only five patients required four or five laser treatments. Macular edema resolved in 90% of patients that required a single laser treatment and in 74% of patients that required multiple laser treatments. Improvement in two or more lines of vision was reported in 46% of patients and vision loss of one or more lines in 16% of patients. Patients who showed worsening of two or more lines after the first laser treatment did not improve with additional laser treatments.23 Nevertheless, laser photocoagulation is still the most proven treatment modality in treating macular edema due to BRVO.
In a study of 30 patients that compared macular grid laser treatment to intravitreal bevacizumab injection in nonischemic BRVO, intravitreal bevacizumab was found to improve visual acuity and reduce central macular thickness more significantly than macular grid laser.24 Short-term studies with bevacizumab treatment were reported to improve visual acuity and central retinal thickness in patients with macular edema due to BRVO.25,26
In a prospective study of patients with BRVO who were treated with bevacizumab, patients showed improvement of both macular thickness and visual acuity. Short duration of disease had a better prognosis than longstanding pathology.27 Furthermore, repeated injections were needed in order to improve outcomes.27,28 In a 12-month follow-up study, only 14% of patients showed resolution of edema after three injections, whereas 20% required repeated injections up to the 12-month follow-up without resolution of edema, with an average of eight injections in 12 months. Patients also showed fluctuations in visual outcome and retinal thickness. The study confirms the need for repeated monthly injections in order to maintain favorable outcome with bevacizumab.29
In a recent study of intravitreal bevacizumab in BRVO with a 12-month follow-up period, visual acuity improved from logMAR 0.53 to logMAR 0.26. Younger age and better pretreatment visual acuity were associated with better outcome at 12 months.30 In another study, visual acuity also improved from logMAR 0.5 to logMAR 0.2 and the central macular thickness decreased in 40%.31 A recent study comparing two doses of bevacizumab (1.25 mg and 2.5 mg) with 24 months of follow-up found that both doses almost halved the macular thickness and that about 70% of patients gained three or more lines of vision.32
In the Branch Retinal Vein Occlusion (BRAVO) trial — a phase 3, multicenter, randomized study using ranibizumab — 397 patients were randomized to receive 0.3 mg or 0.5 mg intravitreal injection of ranibizumab compared to a sham injection control group. At six months, the treatment arms gained 16.6 and 18.3 letters (0.3 mg and 0.5 mg, respectively) compared to a significantly lower 7.3-letter gain in the control group. Fifteen percent to 20% of patients treated with ranibizumab gained three or more lines of vision at week 1, and by six months 55.2% to 61.1% of both treatment groups gained 15 letter of vision, compared to 28.8% in the sham group. The study results show that ranibizumab can result in a rapid and substantial improvement in vision in patients with BRVO.33
A small uncontrolled study, on 20 patients treated with 0.3 mg and 1 mg intravitreous pegaptanib administered at six-week intervals, reported overall improvement of +14 letters in visual acuity in subjects with BRVO over a 54-week period of follow-up. Half of the subjects gained at least three lines of vision by 30 weeks and maintained these results. The visual acuity improvement was paralleled by reductions in retinal thickness and macular volume.34
Finally, a phase 3, prospective randomized, controlled study of a dexamethasone intravitreal implant (Ozurdex, Allergan) compared 700 µg dexamethasone at months 0 and 6, 350 µg dexamethasone at month 0, or sham injection at month 0 in patients with BRVO and CRVO. Dexamethasone led to improvement of three lines or better in vision in 20% to 30% of patients in the first two months, compared to 7% to 12% in the sham group. Peak response was observed after 60 days from the first and second injection. After 12 months of follow up, 30% of patients who received two treatments with dexamethasone implant 700 µg improved in ≥15-letter, 60 days after each injection. Vision gain of ≥15-letters was reported in 39% of patients that received treatment with 700 µg dexamethasone at entry and entered the open-label phase of the study after 12 months of follow up compared to 26% of patients that received the treatment at the open-label phase of the study.
Combination treatment with intravitreal triamcinolone followed by laser treatment in patients with macular edema due to branch vein occlusion was studied in small case studies. One study reported gain of three or more lines of vision in one-third of the patients after six months of follow up and median change of 2.0 lines at six months.35 In a pilot study comparing combination treatment with intravitreal triamcinolone and subthreshold grid laser compared to laser, better results were reported with the combination treatment.36
In summary, both treatments, as we outlined, show improvement in retinal thickness and vision in patients with BRVO. In CRVO, there is no gold standard treatment for macular edema. Laser did not show beneficial effect in patients with macular edema resulting from CRVO, and this has led researchers to seek other treatment modalities. The SCORE-CRVO study reported better results with intravitreal triamcinolone at low doses compared to observation after 12 months of follow-up.8 The CRUISE study showed promising results with ranibizumab in patients with CRVO. No large, long-term, randomized, controlled prospective study has compared intravitreal anti-VEGF treatment to control and to intravitreal triamcinolone in CRVO patients.
Laser continues to be the standard of care in patients with BRVO. The advantages of laser treatment include less-frequent treatments, although, in one study, 50% of patients required more than one laser session and almost 20% required more than three laser treatments. Another potential advantage of laser treatment is the stability of the results after less-frequent treatments and lower cost. Visual acuity results after laser treatment are still not encouraging enough, and this, too, has led to the quest for other treatment modalities.
Nevertheless, the superiority of other modalities has not been proved yet. The disadvantage of macular laser treatment is that it needs to be deferred in patients with significant macular hemorrhages until the bleeding clears significantly to allow treatment, which is the case in about one-third of patients, while intravitreal injections can be started regardless of the presence of hemorrhages. In macular nonperfusion, laser treatment is not useful and is not recommended. Concerns regarding treatment with anti-VEGF agents in the presence of macular ischemia have also been raised.
Anti-VEGF treatment results are encouraging in patients with BRVO, especially with ranibizumab. Anti-VEGF was also reported to increase the central retinal function measured by microperimetry.37 Disadvantages of anti-VEGF treatment include the need for repeated injections, with the concern that repeated injections can result in a decrease in biological response in a subgroup of patients due to tachyphylaxis.38 Other disadvantages include the risk of complications and high cost, especially with ranibizumab. In addition, the number of treatments needed is unclear, as is the duration of treatment. Furthermore, rebound macular edema following cessation of therapy continues to be a problem.
Large, randomized, controlled trials are still awaited to confirm the efficacy and safety of anti-VEGF compared to other treatment modalities in patients with RVO. Combination treatments of anti-VEGF and laser also merit investigation. RP
|Rita Ehrlich, MD, is a vitreoretinal fellow at the University of Auckland, New Zealand. Ruth Axer-Siegel, MD, is professor of ophthalmology and the head of the retina unit at Rabin Medical Center, associated with the Tel Aviv University, Israel. Thomas A. Ciulla, MD, is a partner at Midwest Eye Institute, Indianapolis. Alon Harris, PhD, is a professor of physiology at Indiana University School of Medicine, Indianapolis. Dov Weinberger, MD, is professor of ophthalmology and the head of the ophthalmology department at Rabin Medical Center, associated with the Tel Aviv University, Israel. None of the authors reports any financial interest in any product mentioned in this article. Dr. Ehrlich can be reached via e-mail at firstname.lastname@example.org.|
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