Pam Harrison

August 29, 2013

TORONTO, Ontario — Switching patients to intravitreal aflibercept predictably results in anatomic, but not visual, improvements in patients with wet age-related macular degeneration who have persistent fluid despite treatment with other vascular endothelial growth-factor (VEGF) inhibitors, new research suggests.

"Our end point has always been a dry macula on optical coherence tomography," Franco Recchia, MD, from Tennessee Retina in Nashville, told Medscape Medical News.

"Whether that is desirable has not been proven, but our current goal is to use any agent we can to eradicate all subretinal fluid. Aflibercept is clearly an option for patients who are showing an incomplete anatomic response to other anti-VEGF agents," he noted.

Dr. Recchia and colleagues presented results from a series of switch studies here at the 31st Annual Meeting of the American Society of Retina Specialists.

Hyung Cho, MD, from Georgia Retina in Stockbridge, presented a retrospective chart review of 353 patients with wet age-related macular degeneration who responded suboptimally to ranibizumab 0.5 mg, bevacizumab 1.25 mg, or both. These patients were then switched to aflibercept 2.0 mg. Results of this study have been published in the British Journal of Ophthalmology (2013;97:1032-1035).

Our current goal is to use any agent we can to eradicate all subretinal fluid. Aflibercept is clearly an option.

"We had strict inclusion criteria," Dr. Cho noted. Only patients who had persistent subretinal or intraretinal fluid and who had been treated for a minimum of 6 monthly previous infections were evaluated. In addition, optical coherence tomography scans had to show persistent fluid for a minimum of 3 months before the switch to aflibercept, and the last injection and the initial follow-up exam had to occur 28 to 35 days after the switch. Patients also had to have a minimum of 6 months of follow-up on aflibercept.

From the initial pool of 353 eyes, investigators reviewed 28 eyes from 28 patients. The average age of the cohort was 81 years, and patients had received an average of 20 regular ranibizumab or bevacizumab injections. Over the 6-month study period, patients received a total of 4.4 injections of aflibercept.

"At 1 month, 89% (25 eyes) showed anatomic improvement, and 18% (5 eyes) were dry after a single aflibercept injection," Dr. Cho reported. Central subfoveal thickness improved significantly, from a baseline of 295 µm to 272 µm after a single injection (P < .001). At 6 months, the improvement was maintained at 274 µm (P = .008).

At 6 months, 64% of aflibercept-treated eyes showed anatomic improvement, and one quarter of them were dry. "Visual acuity did not improve at 1 month or at 6 months," Dr. Cho observed, "but treatment was well tolerated and no adverse events were reported."

In a second retrospective chart review, Ashish Sharma, MD, from Retina Consultants of Southwest Florida in Fort Myers, reported on 93 eyes from 83 patients with neovascular macular degeneration who had previously received multiple injections of ranibizumab or bevacizumab and who still had persistent or recurring macular edema, subretinal fluid, or retinal pigment epithelial detachment on optical coherence tomography. The average number of injections per eye was 19 (range, 6 to 34).

Patients were switched to aflibercept and were followed for an average of 14 months. Over the follow-up interval, patients received an average of 9 aflibercept injections.

"We saw resolution of fluid in 42% of the eyes," Dr. Sharma noted. Over the follow-up period, investigators also observed, on optical coherence tomography, anatomic improvement in 20% of eyes, no change in 14% of eyes, and a worsening in 14% of eyes. Follow-up was insufficient in the remaining 10% of eyes.

The average central foveal thickness improved from 368 µm at baseline to 297 µm at 1 month, and was sustained at 316 µm at 1 year. Interestingly, vision improved in 40% of the aflibercept-treated eyes, remained the same in one third of the eyes, and worsened in 27%. Dr. Sharma pointed out that there was a recurrence of previously resolved fluid in 33 eyes when the treatment interval was extended to 8 weeks.

The presenters agree that this appears to be a common finding with intravitreal aflibercept. Most patients require treatment every 4 to 6 weeks, unlike with other anti-VEGF therapies, which can be administered every 8 weeks.

Residual Retinal Edema

Dr. Recchia presented an evaluation of the long-term effectiveness of intravitreal aflibercept in patients with residual retinal edema previously treated with anti-VEGF agents. The investigators studied 40 consecutive patients, treated over a 9-month period, with persistent subretinal or intraretinal fluid despite receiving active therapy with either ranibizumab or bevacizumab.

"Most of them had been treated with a mean of 18 ranibizumab injections," Dr. Recchia reported. At the end of 12 months, "we did achieve a dry macula in two thirds of the eyes" after an average of 3 injections, he added. Most patients required injections every 4 to 6 weeks to maintain dryness; that was extended to every 8 weeks in less than 20% of patients.

At the time of the switch, median central foveal thickness was 272 µm; that dropped to 241 µm at 12 months (P = .008). Median Snellen visual acuity was 20/60 at the time of the switch and at 12 months.

"In most patients, there is an anatomic response to aflibercept, but overall, visual acuity does not seem to change, at least not at 6- or 12-month follow-up," Dr. Recchia emphasized. "Because these are probably more recalcitrant eyes, dosing usually has to be maintained at 4 to 6 weeks, rather than every 8 weeks."

Poorer Outcomes

Although a sizeable proportion of patients with wet macular degeneration and persistent fluid, despite regular anti-VEGF therapy, respond well to intravitreal aflibercept, a handful of patients have poorer outcomes after the switch.

Eric Nudleman, MD, from Associated Retina Consultants in Royal Oak, Michigan, presented a retrospective review of 8 eyes from 8 patients with wet macular degeneration who were treated with monthly ranibizumab for a minimum of 12 consecutive months. Patients had persistent intraretinal or subretinal fluid and were subsequently switched to aflibercept.

"All patients reported subjective symptoms of decreased vision 1 month after the aflibercept injection," Dr. Nudleman reported. In fact, best-corrected visual acuity had worsened by 1 to 2 lines, from a mean of 20/55 before the injection to a mean of 20/64 after the injection.

Mean central macular thickness increased by more than 70%, from 334.6 µm before the injection to 475.2 µm after the injection. "In all cases, increased fluorescein angiographic leakage was demonstrated," Dr. Nudleman noted. One month after a single subsequent injection of ranibizumab, all patients reported a subjective increase in vision and a return to their baseline visual acuity.

"To our knowledge, this is the first description of patients with exudative age-related macular degeneration who were switched to aflibercept, despite good control on another anti-VEG agent, and who had poorer outcomes," Dr. Nudleman said. "Our results suggest that switching to aflibercept in an effort to eliminate all intraretinal or subretinal edema has the potential to worsen clinical outcomes in some eyes."

Session cochair George Williams, MD, from the Oakland University William Beaumont School of Medicine in Rochester, Michigan, noted that physicians are always struggling with patients who do not optimally respond to initial treatment.

He told Medscape Medical News that he is convinced that physicians will see a similar phenomenon with aflibercept, in that there will be patients who do not respond to aflibercept but who, when switched back to other anti-VEGF therapies, will demonstrate similar positive changes.

"The real question is how do we predict which patient will respond to which drug. As of today, we're not that smart," he said.

Dr. Recchia reports receiving speaker's honoraria from a number of pharmaceutical companies, including Regeneron, the maker of aflibercept. Dr. Williams also reports receiving consultant fees from many companies. Dr. Cho and Dr. Sharma have disclosed no relevant financial relationships.

31st Annual Meeting of the American Society of Retina Specialists. Presented August 27, 2013.


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