Watchful Waiting OK in Diabetic Macular Edema With Good Vision

Veronica Hackethal, MD

May 03, 2019

Among patients with center-involved diabetic macular edema (CI-DME) who had good visual acuity, there were no significant differences in vision loss over a 2-year period for those who were initially managed with watchful waiting as compared with those who underwent treatment with laser photocoagulation or aflibercept (multiple brands). Aflibercept is administered as an anti-VEGF (vascular endothelial growth factor) intraocular injection.

The Diabetic Retinopathy Clinical Research (DRCR) Retina Network study is the first to evaluate management strategies for Cl-DME in eyes with good visual acuity. The results were published online this week in JAMA.

"We now know that in patients with good vision and diabetic macular edema, similar to those enrolled in this trial, it's an acceptable strategy to closely monitor patients and initiate treatment only if their vision starts to show signs of decline," first author Carl W. Baker, MD, said in a press release from the US National Institutes of Health (NIH), which funded the trial. Baker is an ophthalmologist at Paducah Retinal Center in Kentucky.

Patients in the observation and laser photocoagulation groups received treatment with aflibercept when visual acuity worsened. About 66% to 75% of eyes in these patients did not require aflibercept during 2 years of follow-up.

"Based on what we've seen in previous, longer-term studies of people with diabetic macular edema, the visual acuity outcomes observed at the end of this two-year study are likely to be maintained if patients continue regular follow-up and treatment as needed over subsequent years," added Jennifer K. Sun, MD, MPH, in the press release. Sun is co-chair of the DRCR Retina Network and is affiliated with Harvard Medical School.

Patients Have the Most to Gain

In a linked editorial, Emily Y. Chew, MD, of the National Eye Institute, NIH, seconded the importance of adherence to follow-up. She also stressed the continued importance of diabetes education, tight glycemic control, and appropriate management of related comorbidities.

Ultimately, patients have the most to gain from this study, she emphasized.

Watchful waiting may spare eligible patients the burden of frequent clinic visits and injections. That, in turn, could decrease healthcare costs and lower the risk for side effects from anti-VEGF injections.

For each injection, the average Medicare cost is $1850. These treatments accounted for an estimated 12% of Medicare Part B costs from 2011 to 2015, Chew points out.

"This approach could not only reduce the increased economic burden associated with intraocular injection therapy, but also could reduce the demands and psychological burden of treatment for diabetic retinopathy for the patients, their families, and society," Chew writes.

In a related article in JAMA Ophthalmology, Tunde Peto, MD, PhD, and Usha Chakravarthy, MD, FRCOphth, PhD, both of Queen's University of Belfast, United Kingdom, voice similar opinions.

Clarifying the Clinical Path in Those With CI-DME but Good Visual Acuity

DME is a form of diabetic retinopathy that affects the macula (the center of the retina), where highest visual resolution occurs. It is the most common cause of vision loss among people with diabetic eye disease in the United States. It occurs as a result of the buildup of fluid in the macula, which can distort vision.

DME can develop at any stage of diabetic retinopathy. Often, patients with CI-DME have good vision. Yet these patients commonly receive anti-VEGF agents, such as aflibercept, that target blood vessel proliferation.

Since 2010, anti-VEGF injections have replaced laser photocoagulation in the treatment of DME. The change in practice occurred largely because of the results of several clinical trials that suggested that anti-VEGF treatment was better than laser photocoagulation in eyes with CI-DME and decreased visual acuity.

But whether these findings apply to patients with CI-DME who have good visual acuity has been unclear.

To evaluate the issue, Baker and colleagues conducted a randomized clinical trial at 91 US and Canadian clinical centers. The study included 702 adults with type 1 or type 2 diabetes, good glycemic control, and at least one eye with normal or near normal vision of 20/25 vision or better.

The mean age of the participants was 59 years; 38% were women; and 66% were white. They were randomly allocated either to undergo treatment with intravitreous aflibercept 2.0 mg (n = 226) as often as every 4 weeks, or laser photocoagulation (n = 240) at baseline with retreatment at 13-week intervals if indicated, or observation (n = 236).

Those in the laser photocoagulation or observation groups who experienced a decrease in vision of at least 10 letters (≥2 lines on an eye chart) at any single visit or 5 to 9 letters (1 to 2 lines) on two consecutive visits were required to begin treatment with aflibercept.

The researchers monitored visual acuity at regularly scheduled follow-up visits. The laser photocoagulation and observation groups received visual acuity testing at weeks 8 and 16 after the start of the study, then every 16 weeks thereafter unless vision worsened. Ninety-two percent of the participants completed their 2-year follow-up visit.

No Differences Between Groups

Results showed no significant difference between treatment groups for the primary outcome of at least a 5-letter (at least 1 line) decrease in visual acuity over 2 years.

Sixteen percent (33 of 205) of the aflibercept group, 17% (36 of 212) of the photocoagulation group, and 19% (39 of 208) of the observation group experienced this outcome (for all, P = .79).

The aflibercept vs laser photocoagulation risk difference was −2% (P = .79); the aflibercept vs observation risk difference was −3% (P = .79); and the laser photocoagulation vs observation risk difference was −1% (P = .79).

There were no significant between-group differences in retinal thickening (P = .07 – .82) or at least 2-step worsening in diabetic retinopathy (P = .05 – .74).

At baseline, the average visual acuity of the participants was 20/20. After 2 years, visual acuity of 20/20 or better was achieved among 77% of the patients with aflibercept, 71% with laser photocoagulation, and 66% with observation.

A significantly greater percentage of the aflibercept group had eyes with 20/20 vision or better compared to those who underwent observation (relative risk [RR], 1.18; P = .03) but not compared to those who underwent photocoagulation (RR, 1.11; P = .15). There was little difference between patients who underwent photocoagulation and those who underwent observation in this outcome (RR, 1.06; P = .40).

There were no cases of endophthalmitis among patients in the aflibercept group. For the aflibercept, photocoagulation, and observation groups, there were similar rates of vascular events: myocardial infarction, 15 patients (7%); stroke, 13 patients (5%), vascular death or unknown death, 8 patients (3%) (P = .28).

Trial participants had reasonably good glucose control, and adherence to follow-up was excellent. Baker and colleagues stress that the results may not be generalizable to patients with suboptimal glycemic control or those with worse adherence to follow-up.

The study was funded by the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. One or more authors reports grants, personal fees, and/or nonfinancial support from one or more of the following: Regeneron, Genentech, Allergan, Novartis, the National Eye Institute, Roche, Clearside, Center for Health Research, Opthea, Sanofi, Appelis, Allergan, National Institute of Diabetes and Digestive and Kidney Diseases, Juvenile Diabetes Research Foundation, the NIH, Kalvista, Current Diabetes Reports, JAMA Ophthalmology, Merck, and/or Optovue. Chew is an employee of the National Eye Institute/National NIH, which supported the Diabetic Retinopathy Clinical Research Network. Peto has received lecture fees from Novartis, Optos, and Heidelberg Engineering. Chakravarthy has received personal fees from Allergan, Apellis Pharmaceuticals, and Novartis.

JAMA. Published online April 29, 2019. Full text, Editorial

JAMA Ophthalmol. Published online April 29, 2019. Full text

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