Protocol V Sheds Light on Managing Mild Diabetic Macular Edema

Medscape Ophthalmology Headlines / 2019-07-30

When it comes to the treatment of diabetic macular edema (DME), ophthalmologists have overwhelming evidence to guide their decision-making—but only up to a point.

DME consists of three clinical subcategories: center-involved DME (CI-DME) with visual acuity (VA) impairment, CI-DME with good vision, and non–CI-DME.[1] Out of these, the prospective data are only substantial and persuasive when it comes to supporting pharmacologic intravitreal treatment of CI-DME with VA impairment with either medications that inhibit vascular endothelial growth factor (VEGF)-A[2,3] or corticosteroids.[4,5] And, until now, the evidence guiding treatment of CI-DME with good VA in the modern era has been relatively scarce. Enter Protocol V, a multicenter, randomized clinical trial designed by the Diabetic Retinopathy Clinical Research Network to help provide guidance in the treatment of these patients.[6]

Investigators enrolled adults with type 1 or 2 diabetes at 91 sites in the United States and Canada. Study eyes had CI-DME (defined as central subfield thickening [CST] ≥ 305 microns in women and ≥ 320 microns in men) confirmed by optical coherence tomography on two different days within a 4-week window, with best-corrected visual acuity (BCVA) of 20/25 or better (at least 79 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). Patients were excluded if they had undergone prior laser photocoagulation or intravitreal injection treatment for DME within the past 12 months.

As part of this study, 702 eyes were almost equally randomly assigned into three arms: observation, macular laser photocoagulation, or aflibercept. The primary outcome was a VA decrease of five or more letters from baseline at 2 years.

Eyes randomly assigned to receive aflibercept received one intravitreal injection at baseline and continued to receive injections at monthly follow-up visits if VA or CST was improving or worsening (defined as a VA change of five or more letters or ≥10% CST change) between either of the last two visits.

Eyes randomly assigned to the laser arm received macular laser at baseline, with retreatment at 13-week intervals if indicated.

The 2-year completion rate, excluding deaths, was 92%, and the median number of visits through 2 years was 18, 11, and 12 in the aflibercept, laser, and observation groups, respectively. The median number of injections through 2 years in the aflibercept group was eight. In the laser arm, 32% received additional macular laser during follow-up.

Investigators anticipated that more patients in the observation and laser arms may experience VA loss than in the aflibercept arm. Therefore, the trial design allowed eyes assigned to observation or laser to receive aflibercept if prespecified VA worsening criteria were met; specifically, aflibercept therapy was initiated if VA decreased from baseline by ≥ 10 ETDRS letters at one visit or by five to nine letters at two consecutive visits. Through 2 years, this endpoint was met in 34% and 25% of eyes in the observation and laser arms, respectively. Among those eyes that lost VA and initiated aflibercept treatment, the median number of injections before the 2-year endpoint was seven and nine in the laser and observation arms, respectively.

Despite 25%-34% of eyes in the laser and observation arms experiencing a clinically meaningful decrease in VA during the trial, at the 2-year time point the percentage of eyes with at least a five-letter VA decrease was 19%, 17% , and 16% in the observation, laser, and aflibercept groups, respectively, with no statistically significant differences between the groups.

The percentage of eyes with VA of 20/20 or better at 2 years was 66%, 71%, and 77% in the observation, laser, and aflibercept groups, respectively

Important Considerations Before Applying Clinically

Protocol V is an invaluable source of information and provides much-needed data to inform clinical discussions with patients who have CI-DME with good vision. Landmark phase 3 trials, such as VISTA/VIVID and RIDE/RISE, have demonstrated the overwhelming superiority of intravitreal anti-VEGF therapy for the management of CI-DME with VA loss, to the point that the decision to initiate treatment on a population basis in such clinical scenarios is now clear.[2,3,7] Comparatively, initiating therapy for CI-DME with good VA requires a more detailed consideration of the risk-benefit ratio on an individualized basis; data from Protocol V can be used to support observation, macular laser, or intravitreal anti-VEGF therapy.

On average, patients enrolled in Protocol V had good control of their diabetes and blood pressure. Furthermore, these patients were selected from clinical practices because of their willingness to attend frequent visits. Therefore, this population may not be representative of patients with diabetes in routine clinical care.

Another challenge in applying Protocol V’s data to clinical practice is that ETDRS BCVA was the sole driver of initiation of anti-VEGF therapy for eyes randomly assigned to observation or macular laser. ETDRS BCVA is a highly specific, rigorous, time-intensive method for determining VA. The majority of retina specialists do not perform this level of VA testing in routine clinical care. Worsening DME in the absence of VA loss was not a trigger in Protocol V for initiation of aflibercept therapy.

Although there is a relationship between CST (amount of DME) and VA,[8] it is an imperfect one, and the field of retina research would benefit from a more comprehensive understanding of imaging biomarkers and how they can be used to guide therapy for each patient