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When it comes to questions about the need for laser in diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), the answers are “yes” and “no,” depending on the clinical scenario, said John Wells, MD.
Generally speaking, laser is considered a valuable treatment, but the most current findings recommend that it be deferred for 6 months after beginning treatment with an anti-vascular endothelial growth factor (VEGF) drug when treating DME and focal laser is reserved for treating non-central DME.
For PDR, laser has a lower treatment burden, ultimately eyes may fare better with ranibizumab.
Focal laser was the go-to therapy for DME until 2010 when the Diabetic Retinopathy Clinical Research (DRCR) Protocol I found that intravitreous injections of ranibizumab (Lucentis, Genentech) with prompt or deferred laser therapy at 6 months provided better results than focal laser when the DME involved the center of the macula.
Prior to those findings, clinicians adhered to the Early Treatment of Diabetic Retinopathy Study (ETDRS) guidelines that recommended focal laser therapy because it reduced the risk of moderate visual loss in patients with clinically significant DME by about 50% at 3 years. However, importantly, any visual improvement was rare.
“It is reasonable to apply the ETDRS guidelines when patients with DME have no central thickening, but observation is also reasonable considering that anti-VEGF therapy is available if the macular center becomes involved,” said Dr. Wells, chairman, Palmetto Health/USC Ophthalmology, West Columbia, SC. “These results are important and should really influence our use of laser.”
Five-year follow-up is available for the DRCR Protocol I study. However, the difference between the ranibizumab-treated patients in the prompt laser and deferred laser group became apparent as early as year 2.
Dr. Wells showed that the deferred laser group had improvements in the letter scores at the 2-year time point that were beginning to be superior to the prompt laser group and at 5 years that difference persisted.
A subgroup analysis showed that in patients with a baseline visual acuity (VA) of 20/50 or worse, the deferred laser group had an average gain of about 17 letters compared with an average of about 10 letters in the prompt laser group.
“In addition, the deferred laser group was more likely to achieve three-line and two-line gains in vision than the prompt laser group,” he said.
Interestingly, these gains in vision occurred despite the fact that similar decreases in the central macular thicknesses were seen on optical coherence tomography in both groups.
A disadvantage associated with the deferred laser group was that more intravitreal injections were needed over the 5 years of the study, i.e., 17 injections versus 13 injections in the prompt laser group.
Another noteworthy observation was that 56% of patients in the deferred laser group never required a laser treatment.
“Adding laser at the initiation of ranibizumab was no better than deferring laser for at least 24 weeks,” Dr. Wells said. “Deferring laser might be associated with greater VA gains through 5 years, especially in eyes with worse VA at baseline.”
He theorized that the larger number of injections in the deferred laser group might have resulted in the better VA or the use of laser in the prompt laser group might have been detrimental to the macula.
The DRCR Protocol T, in which aflibercept (Eylea, Regeneron Pharmaceuticals), bevacizumab (Avastin, Genentech), and ranibizumab were compared in patients with DME, also shed light on the use of laser for center-involved DME.
Patients received similar numbers of intravitreal injections, but significantly (p < 0.001) more patients in the bevacizumab group underwent laser treatment.
“Despite more laser treatment, no differences were seen in the VA among the three groups at the 1- or 2-year time points, indicating that laser did not provide a benefit,” he said.
Subgroup analyses based on a baseline VA of 20/50 or worse and reduction of edema showed that the bevacizumab group was inferior to the other two groups. The aflibercept group with the least amount of laser had the best visual outcomes.
In both the Protocol I and T, persistent DME was problematic, which might be a scenario for use of micropulse laser or targeted panretinal photocoagulation (PRP) for peripheral ischemia, Dr. Wells explained.
Currently, little randomized trial data are available for the former, and the latter did not appear effective.
The bottom line is that focal laser has a role in DME but should be deferred for 6 months and anti-VEGF therapy is the primary treatment for center-involved DME. ETDRS recommendations can be followed in the absence of central macular involvement.
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Protocol S compared PRP with intravitreal ranibizumab in patients with PDR. The results showed that ranibizumab alone was superior to PRP plus ranibizumab in eyes with both PDR and DME at 2 years, but that benefit decreased by the 5-year time point.
Generally, at 2 years, ranibizumab provided better VA outcomes, less visual field loss, fewer vitrectomies were required, and less development of center-involved DME compared with the PRP group. The advantages of PRP were fewer visits and injections and greater cost-effectiveness in eyes without DME initially. More than half of patients in the PRP group needed supplemental laser during the first 2 years of the study (51% versus 14%).
The VA results at 5 years were similar in both groups as were the changes in the letter scores.
The mean changes in the VA over the course of the study in the eyes with baseline DME indicated an early benefit for the ranibizumab group that disappeared at 5 years. In the eyes without DME at baseline, little difference was seen in the VA over the course of the study.
Visual field preservation was significantly greater in the ranibizumab group compared with the PRP group, but that difference began to decrease at 2 years; at 5 years, the ranibizumab benefit was lower but still greater than PRP.
“Despite the fact that the benefits of ranibizumab for vision and visual fields decreased over time, the secondary complications of PDR, such as development of DME, tractional retinal detachment, and the need for virectomy, were less in the ranibizumab group compared with the PRP group over 5 years,” Dr. Wells said.
The vitreous hemorrhage rates were similar in both groups.
Dr. Wells advised that the treatment benefits should be weighed against the increased treatment burden and the risk of non-compliance with ranibizumab monotherapy for PDR.
The general findings were that the mean change in VA was similar in the PRP and ranibizumab groups and the loss to follow-up was high in both groups. The PRP group was associated with a lower treatment burden with similar outcomes.
“Laser still has a role in the management of diabetic retinopathy,” Dr. Wells said. “In DME, focal laser is reasonable for treating non-central DME. When the DME is center-involved, laser should be deferred for 6 months. In PDR, laser is a viable treatment option that carries a lower treatment burden.
“However, the rates of secondary complications of PDR are higher than in eyes treated with ranibizumab,” Dr. Wells concluded.
John A. Wells III, MD
Dr. Wells is a consultant and investigator for Genentech and an investigator for Regeneron Pharmaceuticals.