Insights from anti-VEGF pivotal DME trials
Analyses of data collected in the RISE/RIDE and VIVID/VISTA clinical trials provide important messages about the efficacy and safety of ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron) for treatment of diabetic macular edema (DME).
Reviewed by Marco Zarbin, MD, PhD
Dr. ZarbinAnalyses of data collected in the RISE/RIDE and VIVID/VISTA clinical trials provide important messages about the efficacy and safety of ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron) for treatment of diabetic macular edema (DME).
“We learned from these pivotal trials that the anti-VEGF agents are disease-modifying in that they do not just treat DME,” said Marco Zarbin, MD, PhD, professor and chairman, Department of Ophthalmology & Visual Science, Rutgers-New Jersey Medical School, Newark, NJ. “They also reduce severity of diabetic retinopathy in patients with DME.”
Data also show that visual outcomes are better with anti-VEGF treatment than with conventional focal macular laser photocoagulation, Dr. Zarbin added. Visual outcome seems to be adversely affected if anti-VEGF treatment is delayed for one to two years, even though the edema resolves after delayed initiation of anti-VEGF therapy.
“In addition, analyses of adverse event data demonstrate that systemic risks of intravitreal anti-VEGF injections are real, particularly for patients with high exposure receiving ongoing monthly treatment,” he said.
Disease-modifying benefit
Data on diabetic retinopathy severity graded using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (DRSS) were collected in the ranibizumab and aflibercept DME trials (RISE/RIDE and VIVID/VISTA, respectively). Improvement in diabetic retinopathy was analyzed using the metric of a ≥2-step improvement in the DRSS.
2-Step Improvement in Diabetic Retinopathy Severity Score in Year-1. Courtesy of Marco Zarbin, MD, PhD
In RIDE/RISE, about one third of patients receiving ranibizumab 0.3 mg achieved this endpoint after 1 year of treatment, and this percentage was significantly greater than in the sham-treated control group. The proportion of patients treated with ranibizumab 0.3 mg, who achieved a ≥2-step improvement in the DRSS, increased after 2 years of treatment.
Results with aflibercept in VIVID/VISTA were similar with respect to percentage of patients benefiting, the increase with time, and the superiority compared with controls, Dr. Zarbin said.
The sooner, the better
The design of the RIDE/RISE trials provided insight about the effect of an anti-VEGF treatment delay. In these 36-month studies, patients were initially randomized to monthly injections with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham. After 2 years, patients in the sham group were crossed over to monthly ranibizumab 0.5 mg.
Although best corrected visual acuity (BCVA) in the original sham group improved from month 24 to month 36, it never reached the level achieved among patients receiving ranibizumab since study entry. At month 36, mean BCVA improvement from baseline ranged from 10.5 letters to 14.2 letters across the original ranibizumab groups, but was <5 letters for the sham controls crossed over to ranibizumab after 2 years. Similar results were observed in the VIVID/VISTA trials using aflibercept.
Superiority versus laser
Data on the relative effectiveness of anti-VEGF injection compared with focal macular laser photocoagulation are available from RIDE/RISE and VIVID/VISTA in which the control groups were treated with the laser at baseline followed by sham injections. Reviewing data from follow-up to 1 year in VIVID and VISTA, Dr. Zarbin said the laser-treated controls had “marginal improvement” in BCVA, gaining just 0.2 letters and 1.2 letters, respectively.
Across both studies and for both the aflibercept 2 mg every 4-week and 2 mg every 8-week aflibercept cohorts, mean change from baseline BCVA ranged from 10.5 letters to 12.5 letters. Similar results were obtained for ranibizumab in the RIDE/RISE trials.
Serious safety concerns
The potential for cardiovascular complications in patients receiving intravitreal anti-VEGF therapy is explained by understanding that first, the systemic consequences of VEGF blockade include increased propensity to hypertension and thrombosis, and second, patients with DME are already a high-risk group for cardiovascular events.
“Patients with diabetes are at risk for microvascular and macrovascular complications,” Dr. Zarbin said. “Looking at data on hospitalizations for cerebrovascular accidents and myocardial infarction shows that patients with DME have higher rates of these events than diabetic patients without DME.”
The systemic safety risks of anti-VEGF therapy for DME were evaluated in a meta-analysis by Avery and Gordon [JAMA Ophthalmol. 2016;134(1):21-29]. They used data from patients receiving monthly anti-VEGF injections in the ranibizumab and aflibercept DME pivotal trials.
They found that after 2 years, the groups with the highest level of exposure to intravitreal ranibizumab or aflibercept (patients receiving monthly injections) had about a 3-fold increased risk of all-cause mortality compared with their respective control groups.
“The risk associated with anti-VEGF therapy persisted in a pooled analysis combining aflibercept and ranibizumab patients,” Dr. Zarbin said. “This risk was both clinically important and statistically significant.”
Marco Zarbin, MD, PhD
This article is based on a presentation given by Dr. Zarbin at the 2017 Retina World Congress. He is a consultant to Boerhinger Ingelheim, Coherus Bioscienes, Isarna Therapeutics, Roche/Genentech, Novartis Pharma AG, and Ophthotech.
