Clinical Studies:
DRCR.net Protocol AC
Citation: Jhaveri CD, Glassman AR, Ferris FL 3rd, et al. Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med. 2022;387(8):692-703. doi:10.1056/NEJMoa2204225
Key Points
- Protocol AC is a randomized clinical trial enrolling Type 1 or Type 2 diabetic eyes with central involving macular edema and moderate vision impairment.
- There was no significant difference in outcome between aflibercept monotherapy and bevacizumab first then switching to aflibercept if response was suboptimal.
Objective
To compare visual acuity at 2 years among eyes with center involving macular edema and visual acuity of 20/50 and 20/320 when managed by intravitreal aflibercept monotherapy versus intravitreal bevacizumab first with a switch to aflibercept beginning at week 12 if the response was suboptimal as defined by protocol-specific criteria, replicating a real-world scenario where insurance companies often require step therapy, in which bevacizumab is used for the initial treatment due to its lower cost.
Study Design
Multicenter, randomized clinical trial at 54 clinical sites in the United States. Duration: 2 years.
Study Subjects
- Adults with type 1 or type 2 diabetes with at least one study eye with center involving diabetic macular edema and visual acuity between 20/50 and 20/320.
- Major inclusion criteria: Eyes with type 1 or type 2 diabetes with ci-DME and VA 20/50 to 20/320.
- Major exclusion criteria:
- Eyes that had received anti-VEGF treatment for diabetic macular edema in the previous 12 months
- Eyes that had received any treatment for diabetic macular edema (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids) within the previous 4 months
Randomization Scheme and Interventions
- Adults with type 1 or type 2 diabetes with at least one study eye with ci-DME and VA between 20/50 and 20/320. Study eyes were randomly assigned 1:1:
- 2.0 mg aflibercept
- 1.25 mg bevacizumab + deferred 2.0 mg aflibercept if the eye meets switch criteria
- Follow up schedule: Visits occurred at baseline, every 4 weeks through 1 year, and then every 4 to 16 weeks in year 2 depending on disease progression and retreatment.
- Treatment Algorithm for Both Groups:
- Loading phase: 6 monthly injections, unless VA improved to 20/20, and central subfield thickness (CST) on OCT improved to below threshold to treat
- Maintenance phase: Monthly injections, unless VA and OCT stable over the last 2 visits
- Follow-up phase: Monthly visits while injections are given. Once treatment is deferred for the second time, double the duration between successive visits to a maximum of 4 months. If DME recurs or worsens at any time during follow-up, restart injections.
- Switch Criteria: Starting week 12, study eyes in the bevacizumab treatment group that met all the following switch criteria were switched to treatment with aflibercept:
- OCT central subfield thickness (CST) ≥ a minimum threshold indicating edema (>2 SDs above the average, which is machine and gender specific)
- VA not improved at least 5 letters from the prior two visits
- OCT central subfield thickness (CST) not improved at least 10% from the prior two visits
- VA is 20/50 or worse (at weeks 12, 16, 20) or 20/32 (week 24 or later)
Results
- Study Population: 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Study Completion: 88%.
- Efficacy:
- At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups.
- Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy.
- Primary outcome: change in visual acuity from baseline at 2 years:
- Aflibercept-Monotherapy (N=132 eyes): 15.0±8.5 Letters
- Bevacizumab-First (N=128 eyes): 14.0±8.8 Letters
- Change in central subfield thickness from baseline at 2 years:
- Aflibercept-Monotherapy (N=132 eyes): −192±143 μm
- Bevacizumab-First (N=128 eyes): −198±160 μm
- Safety:
- Prespecified ocular adverse events were infrequent in the two treatment groups.
- Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.
Conclusions
- In eyes with diabetic macular edema involving the macular center and moderate vision impairment, treatment with a bevacizumab-first strategy was as efficacious as aflibercept monotherapy at 2 years and can provide a more economical option.