|UPDATES IN CLINICAL TRIALS IN RETINA
|Year : 2016 | Volume
| Issue : 1 | Page : 38-43
Clinical trials in branch retinal vein occlusion
Tandava Krishnan Panakanti1, Jay Chhablani2
1 Vitreo-retina Consultant, Vasan Eye Care, Hyderabad, Telangana, India
2 Smt. Kanuri Santhamma Retina Vitreous Centre, L.V. Prasad Eye Institute, Hyderabad, Telangana, India
|Date of Web Publication||4-Jan-2016|
Smt. Kanuri Santhamma Retina Vitreous Centre, L.V. Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, Hyderabad - 500 034, Telangana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Branch retinal vein occlusion (BRVO) is the second most common retinal vascular disorder. The management of macular edema has changed considerably over time. The laser is considered the gold standard treatment for over two decades. However, visual recovery with laser is usually slow and incomplete. The advent of intravitreal agents, specifically anti-vascular endothelial growth factors (VEGF) have heralded a new era which promises rapid recovery of vision and quality of vision. Randomized clinical trials have reported optimal results with anti-VEGF agents (ranibizumab, bevacizumab, and aflibercept) compared to laser therapy or steroids. However, nearly 50% of the patients require repeat intravitreal anti-VEGF therapy up to 4 years after initiating therapy to sustain the visual gains. The adverse events (systemic and ocular) of these agents are minimal. Monotherapy with anti-VEGF agents have been found to provide better results than any combination with laser. This review article summarizes evidence from randomized controlled trials evaluating treatment options for the treatment of macular edema secondary to BRVO with a special focus on anti-VEGF therapy.
Keywords: Anti-Vascular Endothelial Growth Factors, Branch Retinal Vein Occlusion, Clinical Trials, Macular Edema
|How to cite this article:|
Panakanti TK, Chhablani J. Clinical trials in branch retinal vein occlusion. Middle East Afr J Ophthalmol 2016;23:38-43
| Introduction|| |
Branch retinal vein occlusion (BRVO) is the second most common cause of retinal vascular disease after diabetic retinopathy. The visual loss in BRVO is due to the resulting macular edema, hemorrhage, and nonperfusion of the perifoveal capillaries. Macular edema is the most common cause of vision loss in BRVO. Treatment options for managing macular edema with BRVO include macular grid laser photocoagulation and intravitreal injections.,,,, Laser therapy improves oxygenation to the treated area causing constriction of the occluded vein and the adjacent arteriole resulting decreased edema. Steroids such as triamcinolone and dexamethasone have antiinflammatory and antiangiogenic properties that inhibit the expression of vascular endothelial growth factor (VEGF) and other proinflammatory cytokines. VEGF is known to promote edema. Various randomized and nonrandomized trials have been performed to evaluate these treatment modalities. This review describes various randomized trials with special focus on anti-VEGF therapy.
| Methodology|| |
A PubMed based search was performed using the keywords: Branch retinal vein occlusion, macular edema, and treatment. Articles published up to August 2015 were reviewed. The filters used included human studies and English language articles. The studies relevant to this review were selected from this search result and have been used to compile this review article.
Grid laser photocoagulation is the mainstay for the management of BRVO with macular edema. This treatment was based on the outcomes of the branch vein occlusion study (BVOS). The BVOS reported spontaneous improvement in about one-third of cases in the first 3 months. Grid laser was considered after a fundus fluorescein angiography after 3 months in eyes which had persistent macular edema and visual acuity below 20/40. At the end of 3 years, the treated eyes gained an average of 1.33 lines compared to 0.23 lines in a control group. A Cochrane database review found that there is a moderate evidence to suggest grid laser at 3 months in eyes with macular edema secondary to BRVO. However, alternate treatment modalities have been tried as the vision recovery in majority of cases is neither sufficient nor rapid. In addition, a network meta-analysis found the outcomes of eyes treated with laser was similar to sham injection.
As the use of laser photocoagulation decreased because the visual gains were poor, intravitreal steroids were used for the treatment of macular edema. The role of intravitreal steroid injections for macular edema due to BRVO have been evaluated in the SCORE trial. There were no significant differences in visual acuity or foveal thickness outcomes between the grid LASER group, 1 mg and 4 mg triamcinolone groups at the end of 1 year. In addition, there was a significant proportion of cases which developed cataract and raised intraocular pressure (IOP) in the 4 mg group.
A sustained delivery, bioerodable dexamethasone intravitreal implant (Ozurdex ®; Allergan, Inc., Irvine, CA, USA) was recently approved by the United States Food and Drug Administration for the treatment of macular edema secondary to BRVO. Advantages of this implant included that it is a sustained drug release impant hence it requires fewer repeat injection and there is a reduced risk of increased IOP. The GENEVA study analyzed the efficacy of Ozurdex ®, in the management of retinal vein oclusions. The study had 3 arms (0.7 mg, 0.35 mg, and sham injection). Peak improvement in visual acuity and retinal thickness was noted after 60 days in the 0.7 mg group after which the vision deteriorated. These gains were significantly higher than the sham group. A repeat injection of 0.7 mg at the end of 6 months also yielded similar results. Eyes treated with sham initially and Ozurdex ® after 6 months had an improvement in visual acuity and retinal thickness but the gains were lower than eyes treated since baseline. The incidence of cataract was 29.8% of phakic eyes (90/302) in 0.7/0.7 mg group, 19.8% (56/283) in the 0.35/0.7 mg group, and 10.5% (31/296) in the delayed treatment group (P < 0.001). The incidence of increased IOP of atleast 10 mmHg maximized 60 days after the implant. The incidence of increased IOP was 12.6% after the first implant and 15.4% after the second implant in the retreated group (0.7 mg/0.7 mg). The cumulative incidence of increased IOP of 10 mmHg or higher at some point in the 1st year in the retreated group was 32.8%.
Elevated levels of VEGF have been demonstrated after retinal vein occlusion. This forms the basis for the management of BRVO with macular edema with intravitreal anti-VEGF injections. The efficacy of ranibizumab in these cases was investigated by Campochiaro et al. Patients with best corrected visual acuity (BCVA) between 20/40 and 20/400, diagnosed with macular edema secondary to BRVO in the last 12 months with no history of treatment and central foveal thickness (CFT) more than 250 µ were subdivided into three treatment groups (sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab). These patients were treated with monthly injections for 6 months with a provision for rescue laser after 3 months if visual acuity did not improve more than 5 letters with CFT being >250 µ with <50 micron reduction in thickness despite 3 injections. At the end of 6 months, there was a statistically significant improvement in visual acuity in the ranibizumab group (0.3 and 0.5 mg) compared to the sham group. The patients noted improved visual functions over a wide field of activities included in the National Eye Institute-Visual Function questionnaire as early as 1 month after the first injection of ranibizumab. Similarly, the reduction in CFT was also significantly better in the ranibizumab group compared to the sham group. The benefits of these gains continued when the patients were followed up for the next 6 months with treatment on a pro re nata (PRN) basis.
In the 2nd year, patients were followed up at least once every 3 months or more frequently if needed with an option of 0.5 mg ranibizumab if CFT was >250 µ. At the end of the 2nd year, visual acuity gains were sustained with a need for 0–3 injections of ranibizumab 0.5 mg. At 50 months follow-up, 50% of patients with BRVO treated with ranibizumab had complete resolution of macular edema whereas the remaining half needed required up to 3 injections a year in order to sustain the original gains in visual acuity. However, the authors suggested using adjunctive therapy if relatively frequent injections are needed after 2 years of ranibizumab therapy.
A Cochrane database review differed with the findings of the branch retinal vein occlusion (BRAVO) study, suggesting that the rescue laser at the end of 3 months similar to the BVOS could act as a confounder. Moreover, the absence of a direct comparison between laser and ranibizumab is another limitation of this study. The clinical outcomes in patients who had achieved disease stability at the end of 6 doses of monthly injections did not vary whether they were followed up with monthly injections of ranibizumab 0.5 mg or treatment on a PRN basis.
The MARVEL study evaluated the efficacy of bevacizumab compared to ranibizumab on a PRN basis for the management of BRVO with macular edema. The study found that PRN administration of either bevacizumab or ranibizumab was effective in reducing macular edema with improvement in visual acuity with 2.53 letters difference between two drugs (ranibizumab 18.08 letters; bevacizumab 15.55 letters). Both treatments also resulted in rapid restoration of anatomy and function which was sustained by PRN treatment with rescue laser therapy in 12/75 (16%) eyes. Another study of the efficacy of ranibizumab compared to grid laser found that ranibizumab provided significant and sustained benefits in terms of visual acuity and reduction in macular edema compared to grid laser.
The efficacy of bevacizumab as a PRN treatment was studied by Hikichi et al. The eligible patients were followed up every 3 months or earlier with no fixed follow-up protocol and underwent reinjection if the foveal thickness was >250 µ or there was persistent or recurrent macular edema affecting visual acuity. They found that gains in visual acuity and foveal thickness with this therapy. Patients required an average of 3.8 ± 1.5 injections over 2 years with a provision for rescue laser at the end of 3 months. The authors suggested that the decreased frequency of injections might be related to greater intravitreal halflife of bevacizumab as noted in the animal models.
Bevacizumab was also efficacious with a treat and extend regime. Patients were given 3 loading dose of the injection followed by a repeat monthly injections until the macula was dry. There was a gradual 2 weeks increment in follow-up injections until it reached 3 months. The gap between injections was reduced by 2 weeks if the fluid reappeared. The visual acuity gains were similar to the BRAVO study. The number of injections required at the end of 1 year was also similar to the BRAVO study. However, the number of hospital visits was much lower and resulting in fewer investigations. This outcome coupled with the lower cost of bevacizumab compared to ranibizumab provided annual savings of $16,663.50 per patient.
A comparitive study found that Ozurdex ® treatment resulted in better recovery of BCVA and greater reduction in foveal thickness at 1-month follow-up compared to bevacizumab. However, these differences disappered by 3 months onward with both the treatments providing similar results. After the initial loading dose, the reinjection rate was higher with Ozurdex ® compared to bevacizumab.
A comparison of the efficacy of bevacizumab to grid laser reported that bevacizumab treatment resulted in better and faster visual recovery. The authors also found that nonresponders who crossed over after 12 months of treatment fared better suggesting alternative treatment modalities in nonresponders. However, a major limitation of studies involving grid laser is a lack of uniformity of laser treatment and absence of objectivity due to lack of evaluation of the grid by a reading center. Systematic reviews have shown that eyes which are treated with anti-VEGF agents from the beginning fare better than eyes which are either observed or treated with other modalities but crossover to anti-VEGF treatment after 6 months of the disease onset. The vision gained in eyes treated with anti-VEGF agents from the beginning was 18.3 letters at the end of 12 months compared to 12.1 letters when the patient was initially treated with sham and crossed over to anti-VEGF agents at the end of 6 months (P < 0.01). This observation indicates that early anti-VEGF treatment provides better results than natural history.
Vascular endothelial growth factors trap/Aflibercept
Aflibercept is a soluble receptor fusion protein with a VEGF binding affinity greater than ranibizumab or bevacizumab with a longer duration of action in the eye. It also binds to other angiogenic factors including placental growth factors that belong to the VEGF family.
The VIBRANT study was a double-masked, multicenter trial to assess the efficacy of aflibercept compared to macular laser in eyes with macular edema secondary to BRVO. Patients in one arm of the study received 6 injections of 2 mg aflibercept, and patients in the other arm received baseline laser. Sham laser or injections were also given in order to ensure masking. Rescue laser therapy occurred as needed after 12 weeks. At the end of 6 months, the eyes treated with aflibercept had more favorable outcomes in terms of reduced edema (aflibercept 280.5 µ/laser 128 µ) or visual recovery (aflibercepept 17 letters/laser 6.9 letters). Outcomes at 52 weeks follow-up indicated that aflibercept injections at 8 weeks interval after the first 6 months helped maintain vision and foveal thickness in the aflibercept arm of the study. Similarly, rescue aflibercept for the patients in the laser arm from 24 weeks onward resulted in substantial improvement in vision and foveal thickness at the end of 52 weeks. Rescue laser in the aflibercept arm was given at 36 weeks in 10.6% of the eys while rescue injection of aflibercept was given between 24 and 48 weeks of the study in 80.7% eyes in the laser arm. This was the first study to directly compare the efficacy of an anti-VEGF agent to laser therapy and show that anti-VEGF was superior. A network meta-analysis of eight randomized control studies comprised approved treatment modalities (laser, ranibizumab, Ozurdex ®, and aflibercept) was previously performed. The authors reported that the probability of being the most efficacious treatment was 54% for ranibizumab and 30% for aflibercept. Similarly, the probability of gaining more than 15 letters was 39% for aflibercept and 35% for ranibizumab. There was no statistically significant difference in the visual outcomes between ranibizumab and aflibercept. These modalities were also reported to be superior to laser and Ozurdex ®.
Is combination therapy better?
Tomomatsu et al. assessed the efficacy of bevacizumab combined with targeted retinal photocoagulation (TRP) compared to bevacizumab alone. In this study, TRP was performed when an area of nonperfusion was >5 disc diameters. Laser was performed in the relevant area with the posterior extent being 3000 µ away from the fovea. Bevacizumab injection was performed 2 weeks after TRP. The authors concluded that the combination therapy help reduce recurrence of macular edema.
The RELATE trial evaluated the combination of grid and scatter photocoagulation 24 weeks after randomization into the ranibizumab group. The authors  found no additional benefits of laser in terms of improvement in vision, resolution of macular edema, or reduced number of intravitreal injections.
The Retinal Vein Occlusion Associated Macular Edema study compared the efficacy of intravitreal ranibizumab to grid laser and combination therapy. In this study, treatment was instituted immediately and duration of follow-up was 6 months. The eyes in the ranibizumab group were treated with 3 monthly injections followed by observation for the next 3 months. The study found that eyes treated with ranibizumab recovered vision faster than the grid laser and the combination group. In addition, there was no distinct advantage of combination therapy over ranibizumab in terms of functional or vision recovery or prevention of recurrence. However, foveal thickness increased in the ranibizumab group whereas it decreased in the grid laser group between months 3 and 6 follow-ups with no associated variation in visual acuity. This suggests that morphological changes precede visual changes in cases of recurrence. However, the study  had a follow-up of only 6 months. Studies have shown that the benefits of grid laser become evident after the 1st year. Hence, longer follow-up would provided stronger conclusions.
Azad et al. compared the efficacy of ranibizumab and laser, bevacizumab and laser with that of laser alone in the management of BRVO with macular edema. Laser was performed in the combined group 7 days after the intravitreal injection. Patients were followed up after 1, 3, and 6 months and retreated if visual acuity decreased by 2 Snellen lines or the CFT increased by more than 100 µ. The authors  found that the gain in visual acuity in the ranibizumab-laser group was significantly higher than the bevacizumab-laser group or the laser-only group. The bevacizumab-laser group also had better gains in visual acuity compared to the laser only group. There was no significant difference in the reduction of CFT in each of the three groups. The authors concluded that a combination of anti-VEGF agents and early laser results in better gains in visual acuity and reduces the number of subsequent injections. The authors noted that performing early laser therapy is difficult because hemorrhages obscure the retinal anatomy. Hence, it is not readily apparent whether the benefits are the result of anti-VEGF agents alone or the result of the combined therapy. A Cochrane database review reported that there is no benefit in performing early (before 3 months) or late laser (after 6 months) in eyes with macular edema secondary to BRVO. A separate review also found uncertain benefits of adjunctive laser in cases of BRVO with macular edema. The European Vitreoretinal Society (EVRS) also found that for medical management, monotherapy with anti-VEGF agents were superior to any form of combination therapy.
The ocular side effects of intravitreal injections include cataract, retinal tear with detachment and endophthalmitis., However, the incidence was lower and may be related to the procedure rather than the drug itself. Systemic side effects include thromboembolic events such as hemorrhagic stroke and myocardial infarction.
The RETAIN trial was conducted to determine the long-term outcomes of patients with ranibiziumab treated for retinal vein occlusions. The trial found serious systemic adverse events in 12/66 (18.18%) cases. The role of ranibizumab could not be proven in any of these cases., Compared to this, the reported incidence of systemic serious adverse events for patients with age-related macular degeneration (ARMD) in the CATT trial was 31.1% for ranibizumab and 39.9% for bevacizumab. However, there was no difference between the two drugs for the development of cardiac or neurological disorders.
A Cochrane database review of all the nonindustry-sponsored randomized controlled trials for ARMD found the risk of developing serious systemic adverse events with ranibizumab was 222/1000 and 240/1000 with bevacizumab (relative risk 1.08; confidence interval: 0.90–1.31). The deaths reported in these trials were unlikely to be the effect of the choice of drug that was injected.
The role of autologous plasmin enzyme in the management of macular edema secondary to BRVO has been studied. Plasmin is a serine protease and has a proteolytic effect on fibrin, laminin, and fibronectin. Laminin and fibronectin are the components of internal limiting membrane (ILM) which help in its adhesion to the collagen fibers of the posterior vitreous cortex. By breaking these adhesions, plasmin induces posterior vitreous detachment (PVD) thereby relieving any traction which might be present. They are also known to increase the oxygen levels in vitreous. A study evaluated the outcomes of an injection of 0.2 ml of plasmin and reported improvements in BCVA and foveal thickness which persisted for 6 months. The authors suggested that the PVD and pharmacological vitreolysis induced by the plasmin may be equivalent to the effect of pars plana vitrectomy without the complications of the surgical procedure.
Sakuma et al. used intravitreal autologous plasmin in the management of macular edema due to BRVO in 26 eyes. PVD was induced after injection in 23 of these eyes whereas the rest had no PVD. BCVA improved irrespective of the induction of PVD suggesting that mechanisms other than vitreolysis might be in play. Electroretinograms of these eyes did not show any signs of retinal toxicity.
Pars plana vitrectomy with ILM peeling is being suggested as an option for the management of macular edema with BRVO. The rationale for this treatment includes relief of traction, improved oxygenation of vitreous and retina thereby preventing photoreceptor loss, removal of inflammatory, and permeability factors such as VEGF and upregulation of epidermal growth factors which help the healing process., The EVRS found vitrectomy with ILM peeling was the most effective management reporting visual gains that were almost twice as high as anti-VEGF agents at 24 months postoperatively. Okunuki et al. found that patients who had high vitreal levels of VEGF and interleukin-8 before vitrectomy had greater macular edema preoperatively and had a significant decrease on foveal thickness at 6 months postoperatively. They also found that high intraocular levels of monokine induced by γ interferon were associated with reduced foveal thickness at 6 months postoperatively. The comparative efficacy of vitrectomy, tissue plasminogen activator (tPA), and bevacizumab was assessed in by Kumagai et al. At 12 months follow-up, the visual outcomes in all the three groups were similar. However, some of the eyes treated with tPA and bevacizumab required additional vitrectomy due to sequelae such as epiretinal membrane and vitreous hemorrhage. While the results of vitrectomy with ILM peeling are promising, further studies are required to validate the efficacy of this approach.
In summary, laser for macular edema in BRVO has been the gold standard of management for more than two decades. However, its limitation includes slow and uncertain visual recovery which has prompted a search for other options. Steroids such as triamcinolone or dexamethasone show promising results but are associated with side effects such as increased IOP and cataract formation. Intravitreal anti-VEGF therapy (ranibizumab, bevacizumab, and aflibercept) has resulted in the best outcomes to date with little direct evidence of ocular or systemic side effects. However, long-term data from the RETAIN study indicate that 50% of the patients require at least three injections even after 4 years of therapy to maintain the visual gains. This has led to the question whether combination therapy in any form might be superior to anti-VEGF monotherapy. In addition, most of the studies seem to suggest that anti-VEGF monotherapy continues to be the best management of macular edema secondary to BRVO.
Various treatment regimens have been tested ranging from the loading dose model in the BRAVO study to the PRN dosing in the MARVEL study. While the former runs the risk of too many injections, the latter could result in undertreatment. Overall, anti-VEGF agents have become the mainstay of management with every patient needing personalized management. While plasmin and vitrectomy seem to show promising results, they require further validation before being accepted as a routine management modality.
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Conflicts of interest
There are no conflicts of interest.
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