July 16, 2016
Results of a 12-month study of eyes with persistent diabetic macular edema (DME) after multiple anti-vascular endothelial growth factor (anti-VEGF) injections indicate that a dexamethasone implant combined with bevacizumab improves visual acuity and macular morphology significantly. The study, published in Retina in 2015, also found that visual acuity changes were not superior to those obtained by continued bevacizumab monotherapy.
Michael W. Stewart, M.D., chair of Ophthalmology at Mayo Clinic's campus in Jacksonville, Florida, and Raj K. Maturi, M.D., with the Midwest Eye Institute in Indianapolis, studied 40 eyes in 30 patients to determine whether a dexamethasone intravitreal implant 0.7 mg (dexamethasone drug delivery system, or dexamethasone DDS) combined with bevacizumab 1.25 mg provides greater benefit than bevacizumab monotherapy in eyes with diabetic macular edema with incomplete response to multiple anti-VEGF injections.
"We know that corticosteroids downregulate VEGF synthesis, but unbound VEGF concentrations after corticosteroid treatment are still 100 times higher than those after anti-VEGF therapy," says Dr. Stewart. "Therefore, combining corticosteroids with anti-VEGF drugs may produce the greatest possible suppression of vascular permeability. Adding triamcinolone to an anti-VEGF regimen fails to incrementally improve DME, but we aren't aware of any trials that pair dexamethasone DDS with an anti-VEGF drug."
Eligibility, assignment and treatment
Eligibility criteria included an age of 18 years or older, best-corrected visual acuity scores between 24 and 78 Early Treatment Diabetic Retinopathy Study letters (20/32 to 20/320 Snellen equivalent), and the presence of DME because of type 1 or 2 diabetes mellitus with a central subfield thickness of greater than 250 µm measured by time-domain optical coherence tomography.
Most of the enrolled eyes had previous treatment with multiple anti-VEGF injections. Fluorescein angiography was performed before enrollment to rule out significant foveal nonperfusion.
Subjects were randomly assigned to one of the two treatment groups in a 1-1 ratio. For patients in whom both eyes met the eligibility criteria, the right eye was randomized to a treatment group and the left eye was assigned to the other group.
The 21 eyes assigned to the combination group received bevacizumab 1.25 mg intravitreally at baseline followed by the dexamethasone implant at month one. Bevacizumab injections were repeated at months two, three, four, six, seven, eight, 10 and 11 when the central subfield thickness was greater than 250 µm and the Early Treatment Diabetic Retinopathy Study visual acuity score was less than 80 letters (20/25 Snellen equivalent). Dexamethasone implants were re-injected at months five and nine according to the same criteria.
The 19 eyes in the monotherapy group received bevacizumab 1.25 mg intravitreally at baseline and month one. Injections were repeated monthly according to the same criteria applied to eyes in the combination group.
Visual acuity and central subfield thickness
The primary endpoints of the trial were an improvement in visual acuity and a decrease in central subfield thickness at month 12. Secondary endpoints included the rapidity of visual improvement (time until + 15 letters) and the number of injections required in each group.
The mean visual acuity changes from baseline to 12 months were similar in the two groups (combined: +5.4 letters; bevacizumab: +4.9 letters; difference = 0.2 letters, 95 percent confidence interval = -5.9 to 6.3; P = 0.75). Eyes that had previously received the greatest number of bevacizumab injections tended to improve more when treated with combination therapy, but lost the most vision when treated with monotherapy.
The study found that combination therapy with bevacizumab and the dexamethasone DDS reduced the central subfield thickness significantly better (-45 +/- 107 µm vs. -30 +/- 100 µm; P = 0.03) compared with continued bevacizumab monotherapy while achieving similar visual outcomes (+5.4 letters vs. +4.9 letters) at one year.
In the 10 patients (20 eyes) who received treatment in each eye, improvements in central subfield thickness at 12 months were significantly greater for the eyes receiving combination as opposed to monotherapy, a difference that far exceeded that seen in patients who had only one eye enrolled. "This fellow-eye comparison provides the strongest evidence for the superior ability of combination therapy with anti-VEGF and dexamethasone-with-bevacizumab therapy to resolve DME thereby warranting further investigation," says Dr. Stewart.
For more information
Maturi RK, et al. A 12-month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema after multiple anti-VEGF injections to assess the efficacy of the dexamethasone-delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina. 2015;35:1604.