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In this article, Dr Simon Taylor discusses results of the key studies for both the ranibizumab anti-VEGF injection and the dexamethasone implant, including the higher BCVA gains achieved for BRVO with ranibizumab in COMRADE-B.
Take-home message: In this article, Dr Simon Taylor discusses results of the key studies for both the ranibizumab anti-VEGF injection and the dexamethasone implant, including the higher BCVA gains achieved for BRVO with ranibizumab in COMRADE-B.
By Michelle Dalton, LS, Reviewed by Dr Simon R.J. Taylor
Visual stability with ranibizumab followed by a p.r.n. re-injection regime achieves better results over a 6-month period than a single injection of dexamethasone,” said Dr Simon R.J. Taylor.
Until the last decade, macular laser treatment was the standard of care for persistent macular oedema secondary to branch retinal vein occlusion (BRVO). Now, two approved intravitreal pharmaceutical therapies are also available: the anti-vascular endothelial growth factor (anti-VEGF) agent ranibizumab (Lucentis, Novartis) and the sustained-release dexamethasone implant (Ozurdex, Allergan); to date, there are no head-to-head studies comparing the two treatments.
“VEGF is the major cytokine released by hypoxic retinal tissue in RVO and thus forms a significant therapeutic target,” Dr Taylor explained.
Ranibizumab was approved in the United States in 2010 for the treatment of visual impairment due to macular oedema following BRVO and central retinal vein occlusion (CRVO) based on the results of two phase III randomized, controlled studies, BRAVO and CRUISE.1-4 In 2011 ranibizumab was approved in the European Union for the same indication. Follow-up patient examinations, which ranged from 1 week to 9 months, showed a mean subfoveal thickness decrease from 513 μm pre-implantation to 376 μm post-implantation. Near complete drying of the macula was achieved in 11 eyes. Six eyes still had significant DME, but follow-up was still relatively early for some of those cases (range, 5 days to 2 months). Visual acuity improved as well in most eyes that were followed for 6 weeks or longer, with some eyes gaining up to 4 Snellen lines. Only 3 eyes had no improvement on optical coherence tomography or in visual acuity.
A second treatment approach centres on corticosteroids, based on their anti-inflammatory effects as well as their ability to reduce vascular permeability. Dexamethasone, a sustained-release biodegradable implant, was approved by the FDA in 2011, based on the results of the phase III randomized, sham-controlled, GENEVA trial.5 The dexamethasone implant was approved in the European Union in 2014.
“Both studies showed the drugs to be effective, but there’s been debate over which one is better because the patient population studies were different,” Dr Taylor said. “Also, the way that the GENEVA (dexamethasone) study was constructed, it’s quite difficult to tell exactly how long the implant was effective.”
It was the hope of the COMRADE-B (Efficacy and Safety of Ranibizumab Intravitreal Injections Versus Dexamethasone Intravitreal Implant in Patients With BRVO) study to address that issue, he reported.
“Although the pharmacokinetic data would suggest a 6-month duration, in clinical practice, the post-marketing experience has been that (dexamethasone) had a more limited duration than that,” Dr. Taylor said. “For me, the major point of the COMRADE-B study was to show what the relative effect of each drug was in a similar patient population.”
COMRADE-B was a phase IIIb, multicentre, randomized, two-treatment arm (ranibizumab versus dexamethasone), double- blind study funded by Novartis AG. It was designed to show that ranibizumab had superior efficacy and safety compared with dexamethasone over a 6-month period.
In the treatment phase, eligible patients received consecutive monthly intravitreal injections with 0.5-mg ranibizumab until visual acuity stability was achieved (defined as a patient’s visual acuity being stable for 3 consecutive monthly assessments performed while on ranibizumab treatment), followed by a p.r.n. re-treatment if there was a decline from stable visual acuity levels, or a single intravitreal dexamethasone (700 μg) and sham injections thereafter.
A total of 244 patients were randomly assigned and received at least 1 dose of study drug 0.5 mg ranibizumab (n = 126) or dexamethasone (n = 118) at 64 sites in Germany, the United Kingdom, Poland, Hungary, and Czechoslovakia. The mean time from diagnosis of BRVO to baseline visit was 57 days. Mean baseline best-corrected visual acuity (BCVA) ETDRS letter scores were 57 and 58, and mean baseline central retinal thickness (CRT) were 540 ± 169 μm and 546 μm for the ranibizumab and dexamethasone groups, respectively. showed superior efficacy to dexamethasone with respect to mean average change in BCVA from baseline to month 1 and through month 6, Dr Taylor said.
Dr. Taylor expected dexamethasone to be a 3-month drug of duration in central RVO, “for BRVO, a 4 to 5 month drug, and for uveitis, a 5 to 6 month drug. So I was a bit surprised to see that in BRVO, the effect is already declining by month 3,” he said, although he did add the improvement seemed to hold steady from month 3 through to month 6.
Over all post-baseline values, patients in the ranibizumab group gained a mean BCVA of 14.2 letters (95% CI; 12.5, 15.7) compared with 9.7 (7.9, 11.4) in the dexamethasone group, which was statistically significant (p < 0.0001).
A greater proportion of patients gained more than 3 lines in the ranibizumab group (61%) than in the dexamethasone group (37%).
Likewise, the percentage of patients who lost at least 1 line was higher in the dexamethasone group than in the ranibizumab group (11.9% versus 3.2%, respectively).
Along with the improvements in BCVA, there was a rapid decrease of CRT in both treatment groups. The mean CRT decreased by 245 μm in the ranibizumab group and by 269 μm in the dexamethasone group after 2 months.
There was then a rebound increase, but this was more pronounced in the dexamethasone group.
“Some people are extremely aggressive in treating to the fullest maximum reduction in central retinal thickness,” Dr Taylor said, “but the data from the COMRADE trial suggest that doesn’t necessarily translate into visual acuity improvement in at least the sort of trend data that we see.”
A total of 135 patients (55%) experienced an ocular adverse event in the study eye, and 156 patients (64%) experienced a systemic adverse event, but most events were not considered to be related to the study drug.
Not unexpectedly, there were significantly more patients in the dexamethasone group with a minimum 10% increase in IOP from baseline compared with the ranibizumab group, but by month 4 had quieted down, according to Dr Taylor.
Adverse events were similar between the two groups as well (with IOP spikes the exception). A planned extension study (to 12 months) is currently running in Germany, Dr Taylor noted.
Dr Simon R.J. Taylor, MA, PhD
Dr Taylor works at the Imperial College London and Royal Surrey County Hospital-NHS Foundation Trust, London, UK.
This article was adapted from Dr Taylor’s presentation during Retina Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr Taylor is on the advisory boards of Allergan, Novartis, and Santen, and receives clinical trial support from Alcon Laboratories, Allergan, Bayer and Novartis.