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Step Therapy Succeeds for Diabetic Macular Edema

Patients with diabetic macular edema (DME) had similar vision outcomes if they received step therapy, you start with a more affordable drug, or upfront aflibercept (Eylea), a randomized trial showed.

After 24 months of follow-up, patients who started with aflibercept had a mean improvement in visual acuity of 15 letters weighed against 14 for patients who started with bevacizumab (Avastin) and switched to aflibercept in accordance with predefined criteria. Central retinal thickness (CRT) also was similar between groups.

Upfront aflibercept was connected with higher rates of serious adverse events (SAEs) and hospitalization for AEs, reported Adam R. Glassman, MS, of Jaeb Center for Health Research in Tampa, Florida, and coauthors, in the New England Journal of Medicine.

“These results expand our knowledge of how and whether clinical outcomes differ by using various anti-VEGF treatment approaches for diabetic macular edema,” the authors said of the findings.

“Previously, the DRCR [Diabetic Retinopathy Clinical Research] Retina Network Protocol T trial showed that eyes with visual acuity worse than 20/50 had better visual-acuity and retinal-thickness outcomes with aflibercept monotherapy than with bevacizumab monotherapy,” wrote Glassman and colleagues. “Unsurprisingly, given these findings, the visual-acuity and retinal-thickness outcomes in today’s trial seemed to favor aflibercept monotherapy on the bevacizumab-first strategy throughout a lot of the first year. However, rescue treatment with aflibercept mitigated the mean visual and anatomical differences that arose from the initiation of therapy with bevacizumab and aflibercept.”

The outcomes have significant financial implications, as Medicare pays $1,830 for an individual dose of aflibercept in comparison with $70 for an individual dose of bevacizumab, the authors noted.

The authors of an accompanying editorial acknowledged that the findings provide support for step therapy, however they noted that the support includes some caveats.

“Possibly the most important nervous about the usage of the bevacizumab-first strategy may be the proven fact that the frequent follow-up of the participants in the initial year of the trial exceeds what often takes invest clinical practice,” wrote David C. Musch, PhD, of the University of Michigan School of Public Health in Ann Arbor, and Emily Y. Chew, MD, of the National Eye Institute in Bethesda, Maryland.

“This concern is particularly pertinent for persons with diabetes, who frequently have numerous coexisting conditions which make it more difficult to allow them to abide by frequent follow-up visits. Missed or delayed follow-up visits in clinical practice you could end up failure to recognize vision loss at or near its onset also to implement a prompt switch from bevacizumab to aflibercept therapy.”

A previous study showed that aflibercept isn’t cost-effective in accordance with bevacizumab for DME, they added. However, “it really is conceivable that some patients who receive bevacizumab first could have irreversible vision loss that may have already been prevented” by promptly switching therapies.

Glassman and coauthors noted that aflibercept and ranibizumab (Lucentis) have FDA-approved indications for DME and that bevacizumab represents a lower-cost, off-label option. All three drugs have demonstrated the capability to improve visual acuity. A trial comparing all three in patients with baseline visual acuity of 20/40 or better showed that aflibercept resulted in better outcomes at 24 months in comparison with bevacizumab and better outcomes than ranibizumab after 12 months.

“Nevertheless, many eyes with baseline vision of 20/50 or worse in the bevacizumab group had good vision outcomes, with 68% having your final visual acuity of 20/40 or better at 24 months,” they described.

Due to the substantially less expensive of bevacizumab versus another two options, more insurers are requiring step therapy that begins with bevacizumab, the authors continued. If the strategy adversely affects visual outcomes for patients with baseline visual acuity of 20/50 or worse is unclear. To handle the problem, members of the DRCR Retina Network performed a randomized clinical trial to compare step therapy and upfront aflibercept in patients with untreated DME and baseline visual acuity of 20/50 or worse.

Investigators at 54 clinical sites randomly assigned 312 eyes in 270 adults to bevacizumab or aflibercept. At a well planned 12-week assessment, patients in the bevacizumab arm were switched to aflibercept should they met prespecified criteria for insufficient benefit or deterioration. The principal outcome was change in visual-acuity letter score at 24 months.

Through the 24 months of treatment and follow-up, 70% of patients who started with bevacizumab subsequently switched to aflibercept. The principal analysis showed an adjusted mean difference of 0.8 letters in visual acuity and only upfront ranibizumab (95% CI -0.9 to 2.5, P=0.37). In both groups, 77% of eyes had a noticable difference of at the very least 10 letters, and 22% of patients in each group had 20/20 vision or better.

The change in CRT averaged -192 m in the upfront-aflibercept group and -198 m in patients randomized to step therapy. The proportion of eyes with CRT below thresholds for DME were similar in both groups at 24 months. The proportion of patients with at the very least a two-step improvement in severity of diabetic retinopathy was 50% in the aflibercept arm and 56% in the bevacizumab-first arm.

The only real case of endophthalmitis occurred in the aflibercept arm. SAEs occurred in 52% of the aflibercept group versus 36% in patients who started treatment with bevacizumab. A number of hospitalizations for AEs occurred in 48% of the aflibercept arm versus 32% of the bevacizumab-first group.

Even though authors didn’t say the analysis supports step therapy as standard of care, the outcomes speak for themselves, said R. Theodore Smith, MD, PhD, of the Icahn School of Medicine at Mount Sinai, who was simply not mixed up in study.

“I believe the conclusion can be an important one and can oftimes be incorporated as standard of care used,” Smith told MedPage Today. “It showed that over 24 months there is essentially no difference in visual outcome between your groups, however in terms of cost, there is a big difference in those protocols.”

“This is exactly what we do at our eye institute,” he added. “We focus on the inexpensive drug, bevacizumab, which has good results, and we follow the individual over an interval of months, maybe around 3 or 4 injections, and observe their progress. If they are making no progress or minimal progress, we’ll switch them to Eylea to see if they’ll do better.”

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    Charles Bankhead is senior editor for oncology and in addition covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow


The analysis was supported by the National Institutes of Health.

Glassman disclosed relationships with Genentech and Regeneron.

Musch and Chew reported having no relevant relationships with industry.

Smith has disclosed relationships with MacRegen and Ora.

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