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Protocol V trial results favor observation strategy for DME with good vision
The DRCR.net Protocol V clinical trial concludes that patients with center-involved diabetic macular edema and good vision can confidently be managed by observation, scheduling anti-VEGF injections only if vision deteriorates.
Protocol V addressed the unanswered question of whether anti-VEGF injections are the best strategy in the common clinical scenario of center-involved DME with good vision. Physicians often treat these eyes based on the good results obtained in clinical trials in which anti-VEGF treatment was evaluated in eyes with reduced visual acuity. Could patients with good vision be spared a costly and burdensome treatment at least until the signs of vision deterioration appear?
To answer this question, a multicenter trial was conducted at 91 clinical sites in the United States and Canada. Between November 2013 and September 2016, 702 participants with center-involved DME and visual acuity of 20/25 or better were randomly assigned to initial management with Eylea (aflibercept, Regeneron) (n = 226), laser photocoagulation (n = 240) or observation (n = 236). In the aflibercept group, injections were administered as needed up to every 4 weeks. In the laser photocoagulation group, patients were treated at baseline with re-treatment at 13 weeks if indicated. In the observation group, no treatment was given at baseline. Patients in the laser and observation groups were monitored closely at weeks 8 and 16 and then at 16-week intervals. They were switched to aflibercept if a decrease of two or more lines at any visit or one line at two consecutive visits was reported.
At 2 years, the rates of visual acuity loss of five or more letters did not differ significantly between groups, and the average visual acuity was 20/20, as it was at baseline, with all three management strategies. Three-quarters of the eyes in the laser group and two-thirds of the eyes in the observation group did not receive anti-VEGF injections over the 2 years of follow-up.
“Each aflibercept injection has an average Medicare cost of $1,850, and all intravitreal injections carry a small risk of endophthalmitis (< 0.1%). Thus, reducing anti-VEGF treatment in these eyes while maintaining good vision has clinical and economic advantages for patients and public health,” the authors wrote.
Close monitoring rather than proactive treatment is bound to positively affect life quality, an aspect that Protocol V did not address, Tunde Peto, MD, PhD, and Usha Chakravarthy, MD, FRCOphth, PhD, wrote in a commentary published in JAMA Ophthalmology.
“It is important to understand the effect of the visit schedules, which differed between groups, and the challenge of frequent visits and injections in the prompt aflibercept therapy group, given that those with diabetes already haves systemic comorbidities that often contribute to a burden of hospital visits,” they wrote.
“Future technology may do a better job of identifying who might benefit from early treatment, before diabetic macular edema affects vision,” Adam R. Glassman, MS, one of the study authors, said in a press release from the National Eye Institute. “But for now, close monitoring of diabetic macular edema in patients with good vision is an appropriate initial strategy as long as they are closely followed and subsequently treated if vision worsens.”
As Peto and Chakravarthy said in their commentary, Protocol V gives physicians the confidence to manage patients with DME and good vision with a vigilant observation approach.
“Such a management strategy would avoid potentially unnecessary introduction of anti-VEGF therapies at a stage of disease that may be amenable to alternative, noninvasive strategies, such as good systemic control,” they wrote. – by Michela Cimberle
Reference:
Peto T, et al. JAMA Ophthalmol. 2019;doi:10.1001/jamaophthalmol.2019.1876.
Disclosures: Baker reports receipt of grants for clinical research from Regeneron, Genentech, Allergan and Novartis. Please see the study for all authors’ relevant financial disclosures.
Regeneron provided aflibercept for the study and funds to the DRCR Retina Network to defray the study’s clinical site costs.
Perspective
Back to TopIntravitreal therapy has become the standard of care for patients with diabetic macular edema. This is clearly beneficial in the case of center-involved macular edema and visual acuity loss. It may not be correct to extrapolate and apply the same approach to patients with good visual acuity. There are arguments in support of variable strategies such as observation and intensive glycemic control and blood pressure control, laser photocoagulation eventually with less intense or subthreshold irradiation, or intravitreal therapy.
It has been shown that even the presence of increased retinal thickness in the central subfield and subclinical edema have a significant risk for progression to center-involved macular edema. However, patients with this condition may still maintain their vision for many years if left untreated. Therefore, we need clear instructions on how to manage our patients properly.
Protocol V demonstrated that in eyes with center-involved diabetic macular edema and good visual acuity, management strategies alternative to anti-VEGF therapy should be initially applied, particularly in the absence of visual acuity loss. Considering patient characteristics and specific needs, either laser photocoagulation as first option or observation as second option are both viable approaches. This also has potential implications in terms of saving costs and possible side effects related to anti-VEGF therapy.
Three-fourths and two-thirds of eyes managed with laser photocoagulation or observation, respectively, did not experience visual acuity loss over 2 years and therefore did not need anti-VEGF therapy. Also, the cumulative probability of anti-VEGF injection is relatively stable in the time frame between month 4 and year 1, giving physicians the possibility to closely observe those patients who may benefit from anti-VEGF therapy due to visual acuity loss. Performing laser photocoagulation at baseline may moderately decrease the need for anti-VEGF injection during the subsequent follow-up as well as decrease the number of injections over 2 years in the case that anti-VEGF therapy is needed due to decreased vision. Possible side effects of thermal laser photocoagulation in the long term should be carefully considered.
Perspective
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We have been looking forward to these results and are very excited now because patients with very good visual acuity are a large group that we never knew how to treat. Many of us just followed them up, but given the proven efficacy of anti-VEGF injections in diabetic macular edema, some of us started to treat them upfront, although there was no evidence that this would be beneficial. What we can see now is that prompt treatment is not needed, provided, however, that patients are closely monitored and have excellent vision. It should be noted that the patients included in this study had a visual acuity of 20/25 or better, and we cannot be sure that the same conclusions would apply to patients with a slightly worse visual acuity, such as 20/32. Central retinal thickness was also very low in the patients included in the study. Only one-third had a retina thicker than 300 µm, and very few were between 400 µm and 500 µm. So, overall, these results apply to patients with excellent vision and a relatively thin retina and should not be unduly extended to patients with a lower vision and a thicker retina. We must be cautious about that in our clinical decision-making.
Another point worth attention is that patients in the observation group who were later started on aflibercept had the same number of injections of the patients treated with aflibercept upfront. We often said that it is important to treat DME aggressively at the beginning, but this is obviously not the case in this group of patients. We can confidently wait without worrying about the final results because there is no toll to pay for deferred treatment. There was a little advantage to the aflibercept group when you look at the area under the curve, but I agree with the investigators that this was too small to recommend prompt treatment in all cases, as you would end up treating many patients who do not need any treatment at all.